Midterm Reviewer Toxicology Lec

PHARMACEUTICAL TOXICOLOGY MT | TERM
Professors: Stephanie Lois Sanchez

Transcribed by: Heidi Jade B. Dato-on
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INTRODUCTION OF TOXICOLOGY
What is Toxicology? § Hippocrates (circa 400 B.C)

• Study of adverse effects of xenobiotics on the living § Added a number of poisons and clinical
systems (in animals and also in human) toxicology principles pertaining to
• Integrates the knowledge and techniques from most
bioavailability in therapy and overdosage
branches of biochemistry, biology, chemistry,
§ Theophrastus (370-286 B.C)
genetics, mathematics, medicine, pharmacology,
§ Student of Aristotle
physiology, and physics
§ Included numerous references to poisonous
• Applies safety evaluation and risk assessment
(Involves estimating quantitavely the potential plants in his famous writing DE HISTORIA
effects of Human health and environmental PLANTARUM
insignificance of the various type of chemical § Dioscorides
exposure) to the discipline § A Greek physician in the court of the Roman
• Toxicologist is trained to examine the nature of Emperor Nero
effects (involves cellular, biochemical and even § Made the first attempt at classifying poisons
molecular mechanism of actions) and assess the as plant, animal and mineral in his book DE
probability of their occurrence of different MATERIA MEDICA which contains
xenobiotic. Therefore as a toxicologists, you will references to some 600 plants
explore the mechanism by which chemicals produce § King Mithridates VI of Pontus
adverse effects in our biological system or living § He drunk regularly a mixture of compaction
system such as humans and animals. (includes 36 ingredients) to protect him from
assassination. Their kingdom was captured
Xenobiotics by the enemies he drank a poison to protect
- Chemical compound and it can be drug, himself but it failed because of his successful
pesticides, carcinogen or any chemical
antidote concoction.
compound that is usually foreign to a living
organism
• Middle Ages
- A xenobiotic is a chemical substance found
§ Maimonides (A.D 1135-1204)
within an organism that is not naturally
§ Treatise or make dissertations on the
produced or expected to be present within the
organism treatment of poisoning from the Insects,
snakes and Mad dogs
History § Famous writings: TREATISE ON POISONS
• Antiquity AND THEIR ANTIDOTES (Describe the
§ Knowledge of animal venoms and plant subject of bioavailability, noting that milk,
extracts for hunting warfare and assassination butter and cream could delay intestinal
§ Ebers papyrus (circa 1500 B.C) absorption. )
o one of the oldest known writings § Catherine de Mecici
o contains information pertaining to § Tested toxic concoction
many recognized poisons, including § Carefully noting the rapidity of toxic instants
hemlock, aconite, opium and metals (onsets of action), the effectiveness of the
such as lead, copper and antimony. compound (potency), the degree of
§ Book of Job (circa 1400 B.C) response of the parts of the body (specificity
• Job 6:4 The arrows of the Almighty are and site of action) and the complaints of the
in me, my spirit drinks in their poison; victim (clinical signs and symptoms)
God's terrors are marshaled against
me.
• Renaissance
§ Paracelsus (1493-1541)
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§ Focused on timely toxic agents as chemical • He studied the mechanism of action
entity emetine (one of the component of
§ "All substances are poisons; there is none ipecac’s group and the use is for
that is not a poison. The right dose amoebiasis
differentiates a poison from a remedy" • Discovered emetine is both myotoxic
§ 1. Experimentation is essential in the and cardiotoxic
examination of responses to chemicals • MYOTOXIC- Causes damaged in
§ 2. One should make a distinction between skeletal muscle and also in the cardiac
the therapeutics and toxic properties of tissue
chemicals • CARDIOTOXIC- damages the heart
§ 3. These properties are sometimes but not • He also studied strychnine (highly toxic
always indistinguishable except by dose crystalline alkaloid). It is colorless and
§ 4. One can ascertain a degree of specificity bitter tasting and usually use as
of chemicals and their therapeutic or toxic pesticides.
effects § Oswald Schmiedeberg (1838 1921)
• On the Miner's Sickness and Other • Published much of the early work on
Diseases of Miners – book (he identify the toxicity of narcotics, methanol,
the toxicity of the mercury and lead glycerol, acrolein, and chloroform.
from goldsmithing and Agricola. Also • Trained many students who later
the etiology of miner’s disease along become toxicologist and
with the treatment and prevention pharmacologist around the globe
strategies. • Modern Toxicology
§ THERE ARE NO SAFE DRUG available IN § Started in late 1950s
THE MARKET. All can cause toxicity § Toxicology is definitely understood especially
§ Percival Pott (1775) the mechanism
§ first report of polyaromatic hydrocarbon § The prevalent use of patent medicines led to
carcinogenicity several incidents of poisonings from these
§ Recognized the role of soot- carbonaceous predicaments.
substance produced during incomplete § 1890s and early 1900s
combustion of coal. § the discovery of radioactivity and vitamins,
§ Scrotal cancer – cleaners of chimney sweep • Use of large bioassays, harmful to
later on developed this kind of cancer and laboratory animals
he reported that when there is repeated § First journal of experimental toxicology
exposure or inhaled on the soot, it can "Archiv fur Toxicologie" in 1930
cause scrotal cancer particularly in male. § Copeland Bill in U.S – response to a tragic
§ These findings led to improved medical consequences of acute kidney failure after
practices particularly in prevention of the taking sulfanilamide in glycol solutions
toxic effect of soot
• Age of Enlightenment- 19th century Different Areas of Toxicology
§ Experimental toxicology accompanied the • Mechanistic Toxicologist
growth of organic chemistry o identifies the cellular, biochemical, and
§ Orfila (1787-1853) molecular mechanisms by which chemicals
• Starts the Forensic toxicology – he used exert toxic effects on living organisms
autopsy material and chemical analysis o Useful in the design and production of safer
systemically as a Legal proof of chemicals and in rational therapy for
poisoning chemical poisoning and treatment of disease.
§ Magendie (1783-1885): emetine and • Descriptive toxicologist
strychnine o Concerned directly with toxicity testing
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o Provide information for safety evaluation and Toxic agents are classified depending on the
also regulatory requirement interests and needs of the classifier. These agents
o They are like part of the FDA may be discussed in terms of their target organs,
• Regulatory toxicologist use, source, and effects or manifestation to the
o involved in the establishment of standards or victim
the amount of chemicals permitted in foods, • TOXIN
drugs, ambient air, industrial atmospheres, o refers to toxic substances that are produced
and drinking water by biological systems such as plants, animals,
o directly involve with the FDA fungi, or bacteria
o Responsibility for deciding on the basis of o May be classified of their physical state,
data provided by descriptive and mechanistic chemical stability or reactivity, general
toxicologist chemical structure, or poisoning potential
• Forensic Toxicology o Toxic substances that are produced by
o Primarily focused on the medico legal on the biological systems such as plants, animals,
harmful effects of chemical in humans and fungi
animals • TOXICANT
o Therefore they are the one who conduct o toxic substances that are produced by or are
autopsy on the poison victims a by-product of human activities
o Hybrid of analytic chemistry and fundamental o Toxic substances that are synthetically
toxicologic principles produced by human activity (pesticides,
• Clinical toxicology insecticides)
o concerned with disease cause by uniquely o Plants that produce toxins: Fungi
associated by toxic substance. They focused
more on identifying the disease such as Spectrum of Undesired Effects
manifestation of signs and symptoms for a o The spectrum of undesired effects of chemicals is
particular toxic substance broad. In therapeutic drug, e.g., each drug
• Environmental toxicology produces a number of effects, but usually only
o focused on the impact of different chemical one effect is associated with the primary
pollutants on the environment especially in objective of the therapy; all the other effects are
biological organisms referred to as undesirable or side effects
• Developmental toxicology o Side effect- Expected side effect in the
o the study of adverse effects on the developing pharmaceutical drug. It is always associated
organism that may result from exposure to with therapeutic effects
chemical or physical agents before o Adverse effect- not common, Unexpected,
conception (either parent), during prenatal undesirable effect. Not all patient is automatic
development, or postnatally until the time of can feel adverse effect
puberty • Allergic Reactions
• Reproductive toxicology o immunologically mediated adverse reaction to a
o the study of the occurrence of adverse effects chemical resulting from previous sensitization to
on the male or female reproductive system that chemical or to a structurally similar to a
that may result from exposure to chemical or chemical that you are exposed to
physical agents o DOSE RELATED
o Study of occurrence of adverse effects for the o Repeated exposure that is structurally similar
male and female with the chemical that you are exposed to
o Focus on the agents of sterility o Chemical allergy described as hypersensitivity,
o Scrotal cancer caused by the soote allergic reaction, sensitization reaction
o When you observed, before you are not allergic
Classification of Toxic Agents to seafood but later on you developed allergic
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reactions with seafood that is because of circulatory system; the blood and hematopoietic
repeated exposure with the substance itself system; visceral organs such as the liver, kidney,
• Idiosyncratic Reactions and lung; and the skin.
o genetically determined abnormal reactivity to a o Muscle and bone are seldom target tissues or
chemical systemic effects.
o NON DOSE RELATED § Affects different organs
o For example in seafood, there are only • Interaction of chemicals
particular dose. o Additive effect
o Even in small amount, let’s say dot size of § most commonly observed when two
seafood there is reaction chemicals are given together occurs when
o Same manifestation with allergic reaction like the combined effect of two chemicals is
rashes equal to the sum the effects of each agent
o Chemical idiosyncrasy given alone
§ The response observed is usually § 1+1= 2
qualitatively similar to that observed in all o Synergistic effect
individuals. § occurs when the combined effects of two
• Immediate toxicity chemicals are much greater than the sum of
o Occurs very rapidly or after single the effects of each agent given alone
administration or exposure to particular § 1+1=3
substance § Produces much greater effects
o Example : STING BY BEE o Potentiation
• Delayed toxicity § one substance does not have a toxic effect
o Delayed toxic effects usually they occur after on a certain organ or system but when
the lapse of sometime meaning in year before added to another chemical makes that
to develop or within months chemical much more toxic
o EXAMPLE: FARMERS (pesticides) repeated § Involves two substances but the other
exposure toxic effect will manifest in years Substance doesn’t have an toxic effect on
certain organ but if combined with another
• Reversible versus irreversible effects substance it makes more toxic
o The ability of that tissue to regenerate largely o Antagonism
determines whether the effect is reversible or § when two chemicals administered together
irreversible. inter ere with each other’s actions or one
o The only organ that regenerates- Liver interferes with the action of the other
o CNS injury is largely irreversible because its § Interfere with others action
cells are differentiated and cannot be replaced. § MOA of Antidotes
o Carcinogenic and teratogenic effects of § Functional, chemical, dispositional
chemicals, once they occur, are usually (involve in ADME in chemical is altered, it
considered irreversible toxic effects depends on how fast the victim or
• Local versus Systemic Toxicity disposition), receptor
o Local Toxicity - Local effects occur at the site of 4 TYPES OF ANTAGONISM
first contact between the biological system and 1. Functional Antagonism
the toxicant. Within a particular site or mostly in o Occurs when two chemicals
skin area exert toxicity counterbalance each other by
o Systemic toxicity- Requires absorption and producing opposite effects on the
distribution of a toxicant from its entry point to a same physiologic unction.
distant site, at which deleterious effects are o For example, the marked all in blood
produced. It affects different organs pressure during severe barbiturate
o Target organs in order of frequency of intoxication can be effectively
involvement in systemic toxicity are the CNS; the antagonized by the intravenous
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administration of a vasopressor agent Characteristics of Exposure
such as norepinephrine or • Route and site of Exposure
metaraminol. o The major routes (pathways) by which toxic
2. Chemical Antagonism / Inactivation agents gain access to the body are the
o simply a chemical reaction between gastrointestinal tract (ingestion), lungs
two compounds that produces a less (inhalation), skin (topical, percutaneous, or
toxic product dermal), and other parenteral (other than
o For example, chelators o metal ions intestinal canal) routes.
decrease metal toxicity and antitoxins o Descending order of effectiveness/can give
antagonize the action of various toxic effects: IV, Inhalational, Intraperitoneal,
animal toxins Subcutaneous, Intramuscular, intradermal,
3. Dispositional Antagonism oral and dermal unless broken
o occurs when the absorption • Duration and frequency of exposure (determine
biotransformation, distribution, or with Controlled animal study)
excretion of a chemical is altered so o Acute - defined as exposure to a chemical or
that the concentration and/or duration less than 24 h. While acute exposure usually
of the chemical at the target organ are refers to a single administration
diminished o Acute exposure by inhalation refers to
o depend on how fast the victim or one continuous exposure or less than 24 h, most
person to do this ADME frequently or 4 h.
o For example madaming laman ang - (Single episode, IV exposure, 24 hours)
tiyan then matagal ang absorption ng o Repeated exposure: subacute, subchronic,
poison chronic
4. Receptor Antagonism § Subacute- Repeated exposure for 1
o occurs when two chemicals that bind month or less
to the same receptor produce less of § Subchronic- 1-3 months (repeated
an effect when given together than the exposure for several weeks or months)
addition of their separate effects or § Chronic- 3 months- years and above.
when one chemical antagonizes the o Repeated exposure is divided into three
effect of the second chemical categories: subacute, subchronic, and
o Receptor antagonists are often termed chronic.
blockers. o Subacute exposure refers to repeated
o For example; ANTIHISTAMINE it will exposure to a chemical or 1 month or less,
bind to histidine decarboxylase o subchronic or 1 to 3 months, and
o Binding of enzyme and active site o chronic or more than 3 months
o Tolerance
§ A state of decreased responsiveness to a Dose-Response Relationship
toxic effect of a chemical resulting from • Correlative relationship of the characteristic
prior exposure to that chemical or a response of exposure and spectrum of effects of
structurally related chemical toxic agents
§ Two major mechanisms are responsible or • Mostly CONSISTENT WITH THE DOSE OR
tolerance: one is due to a decreased AMOUNT OF TOXICANT
amount of toxicant reaching the site where • Racial and age classification
the toxic effect is produced (dispositional • When increases the dose, it will increase the
tolerance) and the other is due to a response or toxic effect of one individual but
reduced responsiveness of a tissue to the sometime different response also will manifest to
chemical a population
§ Pinagbabawal na gamot • Two types
§ Drug addict
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o 1. Individual, or Graded Dose-Response o 2. Quantal Dose-Response Relationships:
Relationship sigmoid dose-response curve
§ characterized by a dose-related § +-1 SD = 68.3% population
increase in the severity of the § +-2 SD = 96.5% population
response § +-3 SD = 99.7% population
§ As you increase the dose of the o Threshold dose responder non-responder at
organophosphate the percent minimally effective dose
inhibition also increase. Therefore
in this response there is directly
proportional relationship between
the response of inhibition and the
dose
• Shape of the Dose-response curve

o Essential nutrients
§ Graded dose-response relationship
o 2. Quantal Dose-Response Relationship- shows a U-shaped curved
Normal or Gaussian Distribution § If you are deficient in vitamins or
§ Population is classified as either a minerals, you will experience different
“responder” or a “nonresponder.” adverse effects
§ QUANTAL means ALL OR NONE § If the increase the dose of vitamins and
§ LD50 - means you are trying to look on minerals to the required dose of vitamins
the 50% died on animal tested by giving then there is no adverse effect exist
a single dose of the substance then it is § If overdose then toxicity happens
expected to death in 50% of the animal
tested
§ Exhibit normal or Gaussian distribution
§ THE BAR
• represents the percentage of
animals that died at immediately at
lower dose
§ More died in average dose compared in
highest dose
§ HYPERSUSCEPTIBLE
• animals that respond at lower dose o Hormesis
§ RESISTANT § Non-nutritional toxic substances
• Animals that died at higher dose • U-shaped curve
• May also impart beneficial or
stimulatory effects at low doses but,
at higher doses, they produce
adverse effects.
• EXAMPLE: For example, chronic
alcohol consumption is well
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recognized to increase the risk of - reflects the limit of the dose response
esophageal cancer, liver cancer, relationship on the response axis to a certain
and cirrhosis of the liver at relatively chemical
high doses, and this response is o Increasing the dose will increase the response
dose related however, D has the maximal efficacy
• low to moderate consumption of
alcohol reduces the incidence of
coronary heart disease and stroke
Variations in Toxic Responses

• Selective Toxicity
o Selective toxicity means that a chemical
produces injury to one kind of living matter
o Threshold without harming another form of life even
§ Minimally Effective Dose though the two may exist in intimate contact
o For example BAYGON only insects are
• Evaluating the Dose-Response Relationship harmed
o Therapeutic Index = : TD50/ED50 • Species Differences
§ Ratio of the dose required to produce toxic o Experimental result may differ in different
effect and dose needed to elicit the desired species
therapeutic response. o Between man and animal
§ The larger the ration between the TD50 and o Identifying the mechanistic basis or species di
ED50, the greater the relative safety of the differences in response to chemicals
drug or tested substance establishes the relevance of animal data to
o Margins of safety = LD1/ED99 human response.
§ Indicator of the magnitude of the difference o For example when tested in animals it
between as estimated expose dose to a developed TUMORS but when tested in
human population and the no observable humans no TUMORS was developed
adverse effect level that is determined in the • Individual Differences in response
experimental animals o Due to genetic differences that has no side
§ Between 1% and 99% responder effects
o GENETIC POLYMORPHISM
o Idiosyncratic
• Margins of Safety and Exposure

o Potency vs Efficacy
POTENCY
- range of doses over which a chemical
produces increasing response
EFFICACY
Mechanism of Toxicity or the ultimate toxicant is the product or the
• When a toxicant enters the biological system, metabolite after the biotransformation of the
commonly it will be delivered in the target molecule toxicant.
which will result to cellular dysfunction which manifest – During biotransformation, pwedeng ma convert
itself into toxicity. ang parent compound into less toxic effect or
• Sometimes, the toxicant will not reach its target pwede rin into more toxic effect.
molecule but rather it can adversely influence the ➢ Increased concentration of toxicant:
biological environment. • Absorption, distribution, distribution to the site of
• Mas worst ang effect if the toxicant did not reach its action, reabsorption, and toxication.
target molecule because it can affect the biological ➢ Decreased concentration of toxicant:
environment, so hindi nya lng masira ang cellular level • Presystemic elimination, distribution away from the
but also the molecular and organ dysfunction which site of action, excretion, and detoxification.
leads to more damage to the skin.
• The complex pathway of toxicity – or the toxicant to ➢ Absorption vs. Presystemic Elimination
exert effect involves the following: – Absorption is the transfer of chemicals from the
site of exposure which is usually on external or
1) Delivery internal body surface into the systemic
– Delivery of toxicant to its target molecule. circulation, ready for distribution.
2) Interact with molecules or alter environment → – Presystemic elimination is another term for first
– The toxicant once inside the target molecule will pass effect. – nung nagkaroon ng first pass
interact with the molecule or alter the environment. effect instead na magkaroon ng distribution –
– Interaction with the endogenous target molecule. nauuna ang metabolism or biotransformation
3) Trigger perturbation in cell function/structure → then bumabalik sa absorption process.
– changing in the normal state of cell function in other – This happens during the transfer from the site
molecules. of exposure to the systemic circulation. The
4) initiate repair toxicant had been metabolized during their
– our body can initiate repair mechanism at cellular level passage to the GI mucosal cells, liver, lungs
or tissue level before distribution.
– if the perturbation is beyond repair or too much
damage, then toxicity will occur. • Factor influencing absorption:
– Our toxicant has many fate – they can exert their (1) concentration – the more concentration, faster
toxicity if our body cannot repair the damage. absorption of toxicants
– Ex. Interaction with carcinogen. At first the body will try
(2) surface area of exposure – if the particle size is
to kill the cells, but if the multiplication of cancer cells
reduced it will increase the surface area therefore
is faster and is already too much for the body to repair
higher dissolution rate then faster absorption.
– then metastasis will occur or the pagdami ng cancer
cells and pwede na kumalat sa other parts of the body. (3) characteristics of epithelial layer – all of the
absorption happens in the small intestine, and the
small intestine is covered or surrounded with epithelial
STEP 1- DELIVERY: FROM THE SITE OF EXPOSURE TO THE
layer – within the epithelial layer is where the
TARGET
absorption of the drugs and other chemicals happen
➢ The intensity of the toxic effect will depend on the and even the food molecules.
concentration and persistence of the ultimate toxicant at
– So the characteristics of epithelial layer will
its site of action.
also determine how fast or slow the
➢ Therefore, the mechanism inside our body (ADME) can
absorption.
actually increase or decrease the concentration of
– Ex. The epithelial layer is damaged because of
toxicant.
ulceration or other diseases so the absorption
➢ Ultimate Toxicant – this refers to the chemical species
is slower.
that reacts with the endogenous target molecule or target
(4) lipid solubility – lipid soluble molecules are
site which critically alters the biological environment that
absorbed most easily into the cells since our epithelial
will eventually initiate the structural or functional
layer is made up of lipids also. So the absorption is
alterations which then result to alteration.
faster if the molecule is also lipid.
– This can be the original chemical in which the
organism is exposed or the parent compound • Presystemic Elimination
– Known as first pass effect – metabolism then bind to the protein bound therefore they will
recirculation or redistribution not reach their target site.
– Decrease toxic effects of chemical reaching their – Protein bound chemicals will not reach their
target site target site therefore it will delay and prolong
– However, it causes damage to the organ it passes. the effect and elimination of toxicants.
Like the GI, liver, and lungs. – since dito sila naga o Specialized barriers
biotransformation. – BBB – blood brain barrier usually lacks the
fenestrae (opening) which prevents the
➢ Distribution to and away from the target access of the hydrophilic chemicals unless it
– This occurs when the toxicants exit the blood is transported by the active transport.
and enters the extracellular phase then reaches – BBB only absorbs lipophilic compounds –
their site of action. that’s why our drugs for CNS and the brain
– Sometimes the toxicants are delivered away are actually lipophilic for easy passage in the
from its target site since in the distribution bbb.
process we have a lot of compartments – so – For the hydrophilic compounds, they need
marami din ang pwedeng pasukan or puntahan active transport before they can enter the
ng ating chemicals and toxicants that bbb.
sometimes konti na lang ang maka reach in the – Same goes with the spermatogenic cells or
target site or worst wala ng maka reach. sperms – they are actually surrounded by
• Mechanisms facilitating Distribution the Target: sertoli cells – they are like bbb and called as
o Porosity of the capillary endothelium blood testes barrier. Hindi sila basta-basta
– Liver and Kidney – their capillary has a very nasisira because they have the same
large opening therefore it permits easy passage characteristics with the bbb so hydrophilic
of protein bound xenobiotics which then can compounds will have difficulty entering the
lead to accumulation of the chemicals in that sperm cells.
organ. o Distribution to storage sites
o Specialized transport across the plasma – Some xenobiotics can accumulate in tissue
membrane where they do not exert their significant
– Ex. Potassium, sodium, ATpase, voltage gated effects therefore decreasing the toxicant
calcium channels, carrier mediated uptake, the concetration in the target site
process of endocytosis and membrane o Association with intracellular binding proteins
recycling facility – can actually help toxicants – There is usually a binding to the non-target
enter specific cells. cellular site which also decreases the
– They can use special transport system, some concentration of the toxicant at a target site.
uses energy to help toxicants enter, some uses o Export from cells
protein to help toxicants. – It is where intracellular toxicant may be
o Accumulation in cell organelles - pH trapping transported back into our extracellular spaces
– This happen to amphipathic xenobiotic – the therefore decreasing the concentration
chemical structure has both hydrophilic and leading to a decrease toxicity.
hydrophobic parts. – Ex. MDR multidrug resistance – MDR protein
– They usually have protonable amine group and usually removed chemicals from the cells, it
lipophilic character that can accumulate in the acts as a transporter to remove chemicals
lysosomes as well as other mitochondria. from the cells.
– When amphipathic xenobiotic can accumulate
or masyadong marami in mitochondria, this will ➢ Excretion vs. reabsorption
cause pH trapping. – Excretion – removal of xenobiotics on the blood
o Reversible intracellular binding then return that into the external environment.
– Organic, inorganic cations, polycyclic aromatic – In the form of urine, feces, any fluid that comes
hydrocarbon – can accumulate in melanin out from us, sweating, tears, breastmilk.
containing cells by binding on the melanin. – Excretion vs. Biotransformation – excretion is a
physical mechanism of removing the toxicants
• Mechanisms Opposing Distribution to a Target while biotransformation is a chemical
o Binding to plasma proteins mechanism of removing the toxicant, because
– The more protein bound is a molecule, this during biotransformation it will alter the
means that our chemicals are more prone to
chemical structure of the toxicant ready for (1) electrophiles – compounds that can accept
excretion. binding electrons.
– During biotransformation, it makes the chemical
(2) free radicals
more hydrophilic – for faster excretion.
– In cases of biotransformation where compound (3) nucleophiles – compounds that can donate
is still lipophilic compound then it has a electrons.
tendency to accumulate in the body and it will
be eliminated very slowly, unlike the hydrophilic (4) redox-active reactants
compound.
– The most reactive metabolite are the
– In lipophilic compound, usually the process in
electron-deficient molecules such as
removing lipophilic chemicals or the compound
electrophiles and the neutral or the cationic
is resistant to biotransformation, the excretion
free radicals.
usually happens in the mammary gland in the
form of breast milk or in the bile and the
– Detoxification
intestinal lumen from the blood.
– It is a biotransformation that eliminates
ultimate toxicant or prevent its formation.
– Excretion: favored with highly hydrophilic compound
– It is converted into lesser harmful products.
o Volatile, nonreactive toxicants diffuse from
– Usually yung mga na convert in the
pulmonary capillaries into the alveoli and are
detoxification have no functional group.
exhale
o Toxicants with no functional group
o Chemicals without functional group +
– Reabsorption - peritubular capillaries
hydroxyl or carboxyl + glucoronic
– After the first pass effect.
acid/sulfuric acid/amino acid = highly
– Metabolism → reabsorption happens if the
hydrophilic organic acids – they are readily
chemicals are delivered via renal tubules or
excreted.
the process of excretion is thru renal
o Nucleophiles
tubules.
– Detoxified thru conjugation thus preventing
– Then diffuse back to the peritubular
the conversion into free radicals and
capillaries - tiny blood vessels in the
biotransformation of phenols, aminophenols,
kidney.
catechols, and hydroquinones to elctrophilic
– Excretion thru kidney – in the kidney there
quinines and quinoneimines
is a reabsorption – its role is to filter out
– Electrophiles involves conjugation with
chemicals that are not needed by the body.
nucleophile glutathione
– Reabsorption can also happen in the GI
o Free radicals
tract by biliary gastric and intestinal
– Superoxide dismutases (SODs) convert
excretion will happen. Pwede din secretion
oxygen to HOOH.
by salivary glands and exocrine pancreas.
– HOOH is reduced to water by cystosolic
Then it will diffuse back to the intestinal
glutathione peroxidase or peroxisomal
mucosa.
catalase
o Depended on the lipid solubility of the
– ONOO- (usually reacts with oxyhemoglobin or
chemical and nonionized molecule
heme-containing peroxidases and albumin)
elimination thru SODS.
➢ Toxication vs. Detoxification – Poxidase-generated free radicals are
– Toxication – other term for metabolic activation. eliminated by electron transfer from
– Happens after biotransformation – it will be glutathione (plays important role in the
converted to harmful or toxic products. detoxification of both electrophile and free
– During biotransformation it will alter the radicals).
physicochemical properties of the chemicals o Protein Toxins - thioredoxin
therefore altering its biological activities. – Extra- and intracellular proteases involved in
– The goal is to convert it to a lesser harmful inactivation of toxic polypeptides.
product. – Renum toxins - They lose their activity when
– During toxication, the toxicant will be thioredoxin will reduce their essential
converted into an electrophile. disulfide bond present in the protein toxins.
o Conversion into
Take Note! o Common with electroph-lic toxicants (nonionic
– Free radicals in the body is both beneficial and and cationic electrophiles and radical cations)
harmful. o Neutral free radicals such as HO, NO, and Cl, C
– Beneficial because they are the ones who – If the interaction is covalent binding and
destroy infections. – destroys bacteria in the strong bond, then it is irreversible. It can
body. permanently alter the endogenous
– Harmful because they accumulate in the body molecules or the target molecule.
and if they are not eliminated. That’s why we
need anti-oxidants in the body to balance the • Hydrogen abstraction
amount of free radicals present. o Neutral free radicals can readily remove H atoms
– The balance of free radicals in the body is from endogenous compounds → free radicals
important for physiological functions. o Radicals remove hydrogen from CH₂ group (free
– If masyado ng marami ang free radicals sa amino acid or amino acid residues in proteins)
body doon maka experience ng oxidative carbonyls
stress – can alter the lipids, proteins, and – These carbonyls can form cross link with
even the dna of the body and eventually DNA and other proteins – can eventually
trigger number of diseases. destroy the DNA and proteins.
– Ex. Natural antioxidants – Vit. C (don’t
necessarily need to take Vit. E). • Electron transfer
o Can oxidize or reduce molecules
STEP 2 - REACTION OF THE ULTIMATE TOXICANT WITH THE

• Enzymatic Reactions.
TARGET MOLECULE
o Act enzymatically on specific target proteins
– The interaction between the ultimate toxicant
and target molecule will lead to dysfunction or
➢ Effects of Toxicants on target Molecules
injury at geological organization of target
• Dysfunction of Target molecules – by inhibiting the
molecules, cell organelles, cells, tissues, and
function of the molecule itself.
organs, worst the whole organism.
o by blocking neurotransmitter receptors or ion
channels, inhibiting enzymes, and interfering with
➢ Attributes of Target molecules
cytoskeleton dynamics
– Nucleic acids, proteins, and membranes.
o covalent and/or oxidative modification on Moieties
– The first target of the ultimate toxicant is always the
of proteins aberrant signal transduction and/or
enzymes responsible for the production of target
impaired maintenance of the cell's energy and
molecules which is nucleic acid, protein, and
metabolic homeostasis – it can inhibit ATP
membranes.
production.
– An ultimate toxicant:
o Covalent binding of chemicals to DNA →
(1) reacts with the target and adversely affects its
nucleotide mispairing during replication.
function,
– It will become a mutated DNA, therefore
(2) reaches an effective concentration at the target site there is a different translation into protein.
– DNA sequence should be perfect since it
(3) alters the target in a way that is mechanistically is the template to copy into an mRNA then
related to the observed toxicity mRNA into proteins.
➢ Types of Reaction: – If mali na or mutated na si DNA, them mali
na ang translation into proteins.
• Noncovalent binding
o Apolar interactions involved with toxicants that
targets. membrane receptors, intracellular • Destruction of target Molecules
receptors, ion channels, and some enzymes. o Toxicants alters the primary structure of
– Apolar interaction – there is a formation endogenous molecules by adduct formation,
cross-linking and DNA fragmentation →
of hydrogen and ionic bonds.
– If the interaction is a noncovalent degradation of target molecules
binding, then it is reversible because it is o Free radicals Cl3COO and HO initiate degradation
not a strong bond. of Lipids by hydrogen abstraction from fatty acids
→ destroying lipids in cellular membrane and
• Covalent binding
generation of endogenous lipid radicals and ➢ Toxicants alters the primary structure of endogenous
electrophiles. molecules by adduct formation, cross-linking and DNA
fragmentation which results to degradation of target
• Non-antigen Formation molecules
o Covalent binding of xenobiotics or Ang cross linking to your DNA or other protein kay it will cause
structural and functional constraints on the linked molecules
metabolites
➢ Free radicals Cl3COO and HO initiate degradation of
o Reactivity by autooxidation
lipids by hydrogen abstraction from fatty acids
o Enzymatic biotransformation
therefore destroying lipids in cellular membrane and
generation of endogenous lipid radicals and
➢ Toxicity not Initiated by Reaction with Target Molecules electrophiles which can harm the structure of our DNA
Nonantigen Formation
1. chemicals that alter H+ ion concentrations in the
➢ Covalent binding of xenobiotics or metabolites
aqueous biophase
➢ Reactivity by auto oxidation
2. solvents and detergents that physicochemically alter ➢ Enzymatic biotransformation
the lipid phase of cell membranes and destroy Usually these are covalent binding of the xenobiotics or the
transmembrane solute gradients metabolites then nagkakaroon ng reactivity by auto oxidation
3. xenobiotics that cause harm merely by occupying a and also enzymatic biotransformation
site or space
Toxicity not Initiated by Reaction with Target Molecules
STEP 3 – CELLULAR DYSFUNCTION AND RESULTANT

– It will not reach the target site but it will alter the biological
TOXICITIES
environment of the organism which then lead to toxic
➢ Toxicant-induced Cellular Dysregulation responses
– Dysregulation of gene expressions – Usually, ang naga initiate nito is the chemicals that alter the
hydrogen ion concentration in the aqueous biophase or
there are solvents and detergents that physicochemically
• Transcription
altered the lipid phase of our cell membranes and destroy
o Xenobiotic interact with the promoter region, the the transmembrane solute gradients or the xenobiotics that
TFs, transcription initiation complex and promoter causes harm merely occupies a site or a space only
methylation 1) chemicals that alter H+ ion concentrations in the
o Xenobiotic mimics the natural ligands when given aqueous biophase
at extreme doses or at critical period during 2) solvents and detergents that physicochemically alter
ontogenesis. the lipid phase of cell membranes and destroy
o It also changes the pattern of cell differentiation by transmembrane solute gradients
alerting TFs which result to overexpressing of 3) xenobiotics that cause harm merely by occupying a
genes site or space
STEP 3 - CELLULAR DYSFUNCTION AND RESULTANT

• Signal Transduction – protein phosphorylation
TOXICITIES
o Chemically altered Signal Transduction with
– Our cells will carry out specialized functions from cell
Proliferative Effect: division or differentiation or apoptosis program cell death
– Facilitates phosphorylation of signal – Our cell has two functions na pwedeng target molecule ng
transducers ating toxicity, it can be cell regulation or signaling and cell
– Promote protein kinases maintenance
o Chemically altered Signal Transduction with • If the toxicant targets the cell that has a function of cell
Antiproliferative Effect: regulation then ang effect is dysregulation ng gene
– Compromise replacement of injured cells thus expression or dysregulation of ongoing cell function
prohibiting survival of cells which leads to • if the role of target molecule is for cell maintenance
apoptosis. then ang pwedeng maapektuhan, it will impair internal
maintenance and external maintenance
STEP 2 - REACTION OF THE ULTIMATE TOXICANT WITH THE
TARGET MOLECULE Dysregulation of gene expression causes - neoplasia,
teratogenesis (damage to the developing fetus), apoptosis
Effects of Toxicants on Target Molecules On-going cell function causes - Inappropriate neuromuscular
activity such as;
• Tremor, convulsion, spasm, cardiac arrythmia
Destruction of target Molecules
• Narcosis, paralysis, paresthesia
Impaired Internal maintenance; eventually it will cause cell ➢ When the toxicant enters the body then this causes
injury and death altering of our protein phosphorylation therefore
• ATP synthesis disrupting protein-to-protein interaction then stopping
• Ca2+ regulation the signal transduction or sometimes inducing
• Protein synthesis abnormal signal transduction or altering the synthesis
• Microtubular function or degradation of signaling proteins therefore will
• Membrane function cause disruption whole cell cycle.
Impaired External maintenance - Impaired function of VIDEO
integrated systems such as Hemostasis which is bleeding in the
organism What we have depicted here is a signal transduction pathway
that gets started with the cholera toxin.
If ang naapektuhan ng toxicant is the cell with cell maintenance And we've talked about signal transduction pathways in other
function then there is a possibility that the cell can survive videos, but it's really this idea that you would have molecules
outside of the cell that would interact with receptors on the
Toxicant-induced Cellular Dysregulation surface of the cell that would then create a whole chain reaction
– ang gina affect is the cell regulation or signaling therefore of events that would cause that cell to do something.
deactivating the specific receptor linked to our signal And so what's happening here is, if you were in the unfortunate
transducing networks situation, and this is not something that you would wish on
– When you say gene expression this occurs primarily in anyone, if they were to have the cholera bacteria in their gut, so
transcription and synthesis storage or release of our let's say that this is the cholera bacteria, that cholera bacteria in
extracellular signaling molecules your intestines will release the, what we can call the cholera
– Transcription is transcribing DNA to mRNA and this toxin.
transcription process is usually controlled by our And here it's depicted in very abstract fashion by a circle on top
transcription factors or TF, also the regulatory or promotor of a triangle. That's not what it actually looks like.
region of our gene It's a protein complex with various protein subunits. It's just
Dysregulation of gene expressions drawn this wayso that we can think about this triangle part
During Transcription interacting with this receptor on the epithelial cell.
➢ Xenobiotic interact with the promoter region, the TFs, And so what happens is this cholera toxin, it will interact with
transcription initiation complex and promoter this ganglioside receptor. You don't have to know the details
methylation here, really just the idea of what's going on.
➢ Xenobiotic mimics the natural ligands when given at And then once it does that, when you see these arrows on these
extreme doses or at critical period during ontogenesis transduction pathways, you could view it as that is going to
activate the next step, or sometimes you might say might
When you say natural ligands ito ay ions or neutral molecules promote the next step or make it more likely to happen.
that can bind to a central metal atom or an ion, natural ligands But what then happens is, is once this thing has interacted, the
act as lewis base or electron bare donors A part of the subunit goes in, interacts with a G-protein. You
– and central atom acts a lewis acid which is an electron pair don't have to know all the details here, but G-proteins are
acceptor something that you'll see
– In other words, when you say ligands both lewis base and in a lot of signal transduction pathways. There's not just one G-
lewis acid protein. There's a whole family of proteins called G-proteins.
When you say ontogenesis refers to the development of the And you can view them as molecular switches. They can get
individual organism or anatomical, behavioral earliest stage to turned on and off based on how they're interacting with other
maturity molecules. Their conformation, their shape changes, and so that
➢ It also changes the pattern of cell differentiation by might activate or deactivate them. But you can see, you can
altering TFs which result to overexpressing of genes follow these arrows, and you can see what eventually happens.
Signal transduction And you don't have to know every detail here.
– Ang gina affect niya is on the extracellular Eventually, it leads to adenylate cyclase, then cyclic AMP, then
signaling molecules such as growth the protein kinase gets involved. But the end result from this
factors, cytokines, hormones, pathway is that you have these ions being released from this
neurotransmitters that eventually it can epithelial cell. And with that, that causes the water to leave the
activate the TF receptor and intracellular cell, and that's what causes diarrhea.
transducing network So the toxin gets your gut cells, gets your intestinal cells to start
releasing water, so then you're going to have very, very, very
➢ Signal transduction is done by interacting proteins bad diarrhea. So that's the big picture, but now we can think
thru protein phosphorylation so when the signal about what might happen in certain situations.
transduction interacts with the protein it will give So if I were to ask you, let's say this epithelial cell somehow had
boomerang action it will trigger another activate a mutation, so its ganglioside receptor does not interact well
another protein with the B subunit here, with the cholera toxin.
What would happen then? Pause this video, and try to think In summary, when a toxicant affects signal transduction then it
about that. will also affect the specific cell as a whole
All right, so for whatever reason,this epithelial cell had a
ganglioside receptor that was a little bit different, and it couldn't Signal transduction
interact as efficiently with the cholera toxin. Well, in that ➢ Chemically altered Signal Transduction with
situation, this, this activation would not be happening or at least Proliferative Effect: continues growth or increase in
would not be happening as efficiently. And so someone with that numbers
type of a ganglioside receptor, • Facilitates phosphorylation of signal
there might be some other negative side effects, but they transducers
actually would not get as bad diarrhea – Sometimes yung xenobiotics will promote
from the cholera toxin because these whole signals transduction continuous growth of cells, ito yung
pathway would not be happening or would not be happening as nangyayari in promotion of mitosis also
strong. tumor formation
Now on the other hand, it turns out that there's molecules that • Promote protein kinases (donating molecule)
can disrupt this signal transduction pathway. So, what we have – It will allow certain TF or transcription
right over here, this is an opioid receptor. And if it gets activated, factors to bind to DNA while inhibition of
then it will activate another G-protein. This one is different than phosphatases’ will appear to be the
the one here, but it's part of that same family. And when you underlying mechanisms of our mytogenic
see this type of thing, when you see a line with this flat head effect of the various chemicals or
instead of an arrow, that means it's inhibiting that process. oxidative stress or uv eradiation
So, for example, this opioid receptor is receptive to a molecule ➢ Chemically altered Signal Transduction with
known as enkephalin. Once again, you don't have to know that. Antiproliferative Effect:
But what you should know is that, okay, you have this molecule • Compromise replacement of injured cells thus prohibiting
outside of the cell that can interact with the opioid receptor, survival of cells which leads to apoptosis
which will then activate a G-protein, and what's interesting is – Kapag walang antiproliferative effect then
that this G-protein is actually an inhibitor of this step right over wala ding mitosis meaning di ma replace
here. yung mga damage and injured cells
And so, if you have cholera and the cholera toxins in your gut,
but you also expose those epithelial cells to enkephalin, Dysregulation of Cellular Activity
well, that might make the diarrhea a little bit less bad. Because – it targets the specialized cell by disrupting any steps in
if this gets disrupted or at least if it gets inhibited, then the rest signal coupling
of this pathway will not happen, or it will not happen quite as – It can cause dysregulation excitable cells ito yung mga cells
strong. ng neurons ng skeletal cardiac and even smooth muscles
So that leaves another question. If there was some mutation in and usually controlled by transmitters and modulators
the opioid receptor here, so it wasn't as good at binding to
enkephalin, what would be the end result? So if your opioid Dysregulation of Electrically Excitable Cells
receptor is somehow not as receptive to enkephalin, well, then The alteration of ongoing cellular activities are due to the
enkephalin will not be as effective at being able to stop this following;
signal transduction pathway because the enkephalin will not be
able to bind with that opioid receptor. 1. Concentration of neurotransmitters - since our
And so this inhibition will not occur, and so you would just have xenobiotics altered synaptic levels by interfering with
the regular transduction pathway from the cholera toxin their synthesis, storage, release or removal of the
occurring, which results in diarrhea. So I'll leave you there.The vicinity of the receptors
big thing to appreciate is when you see these pathways, arrows 2. Receptor function - our xenobiotics can be agonists
you can view as activation, or they're leading to the next step. with our ligand binding site which xenobiotics can
And these lines with these flat heads, mimic your ligand or they can be antagonist but do not
this is about inhibition. And it's pretty typical to see questions, activate the receptor. So, this activators and inhibitors
and, especially if you're a scientist, you might construct these of receptors are usually not involved with the ligand
pathways. But you'll also get questions on, hey, if there's a binding
mutation on something that is activating part of the pathway, Activators and agonists - mimics
what will happen? And then the pathway won't happen as much Antagonist and inhibitors - block the physiological
or maybe at all. And if there's a mutation in something that responses of ligands
inhibits the pathway, what would happen? 3. Intracellular signal transduction - it affects your voltage
Well, if there's a mutation that makes something that would gated sodium and potassium channels then alter
regularly inhibit a pathway less functional, then it won't be able neuronal and muscle activity
to inhibit the pathway as much, and so the pathway will be less 4. Signal-terminating processes - done by removal of cat
inhibited. ions thru your channels by transporters that may lead
to prolong excitation
Dysregulation of Activity of Other cells - Kupffer cells
– Non excitable cells such as exocrine secretory cells
– Itong Kupffer cells kay ito yung mga specialized cells
that are localized in liver or within the lumen of liver
sinusoid and also pancreatic beta cells.
• Nicotine acts as an activator for Acetylcholine nicotinic

receptor then its effect is muscle fibrillation and paralysis
• For antagonist naman which is an inhibitor, Leukotoxin it
affects acetylcholine on Nicotinic receptor by muscle
paralysis
STEP 3
Impairment of Internal Cellular Maintenance: Elevation result to:
Mechanisms of Toxic Cell Death ➢ Depletion of energy reserves by inhibiting the
- If the target molecule affects the cell maintenance function ATPase used in oxidative phosphorylation
- Usually, when the toxicant affects internal cellular ➢ Dysfunction of microfilaments - Actin
maintenance, they may cause cellular death or apoptosis → Microfilaments usually assists in cell movement
and they are made up of protein called Actin
1) DEPLETION OF ATP → Actin works with another protein called myosin to
- ATP is very important in biological system special in produce muscle movement and it also involves in
different biochemical reactions cell division and cytoplasmic streaming (mitosis,
- ATP is a source of energy in different processes in the body meiosis)
➢ ATP is produced during oxidative phosphorylation or → Depriving some organelles with its needed
also termed as electron transport chain which is the substances
last step of the processes ➢ Activation of hydrolytic enzymes
➢ In oxidative phosphorylation the main goal is to produce → Ang ginagawa nya is to do hydrolysis therefore
ATP aside from that the by-product is oxygen destroying the structures of different important
➢ Oxidative Phosphorylation involves 4 complexes substances
➢ The xenobiotics can alter the processes in any step in ➢ Generation of ROS (Reactive Oxygen Species) and
the 4 complexes RNS (Reactive Nitrogen Species)
We have different inhibitor or xenobiotics (A, B, C, D) → the generation of RO(N)S may lead to
Example: hypercalcemia
• A - will affect your complex 1, it will interfere delivery of ➢ MPT: Necrosis and Apoptosis outcome
hydrogen → MPT (Mitochondrial Permeability Transition)
Diba the main purpose of complex 1 is to pump out → MPT is the result of calcium influx and
hydrogen, so that hydrogen will serve as a fuel for your accumulation of water that eventually disrupts the
ATP ATP production these instances will lead to cell lysis
• B - affects complex 2, then majority it will inhibits the or cell death, may result to necrosis and apoptosis
transfer of electron that will eventually inhibits production • Mitochondrial insult (damage) may lead to
of oxygen inactivation of ATP synthase and influx of the
• C - affects complex 3, then it will interfere the oxygen calcium leads to more production of more ROS
delivery to terminal electron transporter such as and RNS
cytochrome oxidase • DNA damage will induce the stabilization and
• D - affects complex 4 totally it will inhibit the oxidative activation of p53 protein, will also increase the
phosphorylation process. This is by direct inhibition of expression of bux, puma, noxa (group of proteins
ATP synthase or thru interference of ADP delivery or it that controls mitochondrial events of cell death
will interfere with the inorganic phosphate delivery, and • Death receptor stimulation it can activate the ca
lastly deprivation of ATP to its driving force such as activation then it will increase the expression of
protons and hydrogen ions bid
→ RO(N)S, Bux, Puma, Noxa, Bid will either promote
2) SUSTAINED RISE OF INTRACELLULAR CALCIUM the MPT it may inhibit cytochrome c, smac or the
AIF release second mitochondria derived activator of
- The intracellular calcium levels are highly regulated and caspases
maintained by impermeability of plasma membrane also by → SMAC - second mitochondria derived activator of
the different transport mechanism that can remove calcium caspases
from cytoplasm → AIF - flavoprotein which is located at the inner
- Toxicants that induces elevation of the cytoplasm calcium mitochondrial membrane that is release early after
levels usually promotes calcium influx thru ligand gated oxygen glucose deprivation
channels in neurons, voltage gated channels, through the → If MTP develops in few mitochondria then it will
pores, across damaged cell membrane, mitochondria, initiate autophagy, it is the body’s way of cleaning
endoplasmic reticulum or by inhibiting calcium efflux from out damage cells to regenerate new and healthier
the cytoplasm
cells. As a result, pwede pang maka survive ang - Direct Repair
cells. » DNA photolyase dna modification can reverse may
→ However, if MTP develops more numbers in - Excision Repair removal of damage base nucleotide
mitochondria in our system then it will trigger the from dna
caspase activation » Base repair -
→ it promotes proteolytic cleavage of proteins, usually - Damaged base is recognized by DNA-glycosylase
inactivates many proteins in the system therefore (hydrolyzes the N-glycosidic bonds) > modified base
resulting to apoptosis creates the apurinic and apyrimidic site in the DNA >
→ If MTP is developed in all of mitochondria then it may AP endonuclease recognized the AP site which then
result to ATP depletion then, nagkakaroon ng hydrolyses the phosphodiester bond adjacent to the
necrosis abasic site > abasic sugar is replaced with correct
Ato depletion then nagkakaroon na ng necrosis it will kill the nucleotide by the DNA polymerase and sealed by DNA
tissue of the biological system ligase
STEP 4 - REPAIR OR DYSREPAIR Include several unlike with mito dna more prone to damage
→ Either the body initiate repair or it will result the damage to usually konti lang ang instances na pwedeng marepair ang
our higher levels of the biological hierarchy mitochondrial dna
→ If the dose of the toxicant is too much then it may result to
dysrepair Step 4 - Repair or Dysrepair
Molecular repair
1) Molecular repair Repair of DNA
Repair of Proteins »
➢ Oxidation of thiol groups can be reserved by Excision Repair
enzymatic reduction catalyzed by thioredoxin and Nucelotide repair
glutaredoxin - ATP-dependent nuclease recognized the distorted
→ Thioredoxin - reduces essential disulfide double helix > exises the damaged DNA nucleotide >
bonds found in our toxins excised section is restored by insertion of nucleotides
→ Glutaredoxin - serves as antioxidant in our into the gap by DNA polymerase and sealed in placed
ROS and free radicals by DNA ligase
➢ Oxidized hemoglobin by electron transfer from » Recombinational Repair
cytochrome b5, regenerated by a RADPH-dependent - Results in two homologous but dissimilar DNA
cytochrome b5 duplexes
➢ Damaged protein can be refolded or degraded with occurs when excision fails to occur before dna replication
the help of chaperone proteins begins
→ Also termed as heat shock proteins used to
synthesize new protein in response to protein Polymerase that unable to initiate its function daughter strands
denaturation kay pag sinabing decombination yung dna strand
➢ ATP/ubiquitin-dependent proteolytic system is
specialized in controlling the level of regulatory • Step 4 - Repair or Dysrepair
proteins eliminates intracellular protein Cellular Repair
→ Usually, eliminates the damage or mutated • Repair of damaged neurons
intracellular protein - Peripheral neurons with axonal damage are repaired by
➢ Eliminated by proteolysis in lysosomes macrophages and Schwann cells are type of glial cells
pf periperal nervous sys helps forms our myelin sheath
STEP 4 - REPAIR OR DYSREPAIR surround our neurons envelopes then rotates acon
Molecular repair forming kapag myelinated are well protected transfer
• Repair of Lipids ng mga information to communicate without the
- Peroxidized lipids are repaired by complex process myelin sheath then there will be mix match of
involving series of reductants, glutathione peroxidase, information
and glutathione reductase NaDPh lipid repair - Specific cells of our immune system macrophage our
• Repair of DNA immunity the first defenses of immune system antigen
or foreign materials and hematopoiesis also growth Macrophages and leukocytes in the ste of injury undergoes
factors activates schwann cells to proliferate damage respiratory burst that produces free radicals and activated
to cns are irreversible large number reserved enzymes
compensate taking over neuron - Altered Protein Synthesis : Acute-phase Proteins
Tissue Repair » IL-6, IL-1, and TF increase or decrease the transcriptional
made up of specialized cells capable of multiplying then it will activity of genes encoding certain proteins - positive and
be reversed of apoptosis and necrosis regeneration of tissue negative acute-phase proteins
Full value of repair for tissues bone marrow respiratory gi
epithelium and also epidermis of skin dividing cells hepatic and - Generalized reactions
renal parenchymal cell ineffective non replicating cardiac cells » May evoke neurohormonal responses
• Apoptosis • Mechanisms of Adaptation
- Causes cell to shrink as its nuclear and cytoplasmic - 1. diminished delivery of the toxicant to the target
materials condense, and then breaks into membrane- - 2. decreased size or susceptibility of the target
bound fragments that are phagocytosed without - 3. increased capacity of the organism to repair
inflammation itself
- Also intercept the process leading to a neoplasia by - 4. strengthened mechanisms to compensate the
eliminating the cells with potentially mutagenic DNA toxicant-inflicted dysfunction
damage
Step 4 - Repair or Dysrepair

• Tissue Repair
• Proliferation: Regeneration of Tissue Loss cells the
reintegration of newly formed triggered by mitosis
- Replacement of cells by Mitosis
» Intracellular signaling is turned on and expression of
numerous genes is increased
- Replacement of the Extracellular Matrix
» Composed of proteins, glycosaminoglycans, and the
glycoprotein and proteoglycans
» Stimulated by the TGF-beta
• Step 4 - Repair or Dysrepair

Tissue Repair
• Side Reactions to Tissue Injury
- Inflammations
» Cells and Mediators
• Initiated by resident macrophages secreting cytokines such as
TNF-alpha and IL-1 in response to damage
> stimulates the stromal cells to release mediators that induce
dilation of local microvasculature and cause permeabilization of
capillaries
Endothelial cells facilitates the eggress of circulating
leukocytes into the injured cells
• Step 4 - Repair or Dysrepair

Tissue Repair
• Side Reactions to Tissue Injury
- Inflammations
» Inflammation produces Reactive oxygen and nitrogen species
• Repair of DNA
❖ Direct Repair Video presentation
➢ DNA photolyase
The DNA in just one of your cells gets damaged tens of
- it is directly involved in the effects of UV light or
thousands of times per day. Multiply that by your body's
UV damage.
hundred trillion or so cells, and you've got a quintillion DNA error
- For instance, if the DNA is damaged by the UV every day. And because DNA provides the blueprint
light, then the enzyme photolyase will reverse the for the proteins your cells need to function, damage causes
effects or will do DNA modification. serious problems, such as cancer. The errors come in different
- The nuclear repair will include several repair forms. Sometimes nucleotides, DNA's building blocks, get
mechanisms. damaged, other times nucleotides get matched up incorrectly,
- Unlike the mitochondrial DNA, are more prone to causing mutations, and nicks in one or both strands can
damage and usually konte lang ang instances na interfere with DNA replication, or even cause sections of DNA to
pwede pa natin ma repair yung mitochondrial get mixed up.
DNA. Fortunately, your cells have ways of fixing most of these
problems most of the time. These repair pathways all rely on
❖ Excision Repair specialized enzymes.
Different ones respond to different types of damage. One
- It involves either a removal of damage base or
common error is base mismatches. Each nucleotide contains a
removal of an entire nucleotide from the DNA.
base, and during DNA replication, the enzyme DNA polymerase
➢ Base repair is supposed to bring in the right partner to pair with every base
o Damaged base is recognized by DNA- on each template strand. Adenine with thymine, and guanine
glycosylase (hydrolyzes the N-glycosidic with cytosine. But about once every hundred thousand
bonds) → modified base creates the apurinic additions, it makes a mistake. The enzyme catches most of
and apyrimidic site in the DNA (depending the these right away, and cuts off a few nucleotides and replaces
base that was damaged) → AP endonuclease them with the correct ones.
recognized the AP site which then hydrolyses And just in case it missed a few, a second set of proteins comes
the phosphodiester bond adjacent to the behind it to check. If they find a mismatch they cut out the
abasic site → abasic sugar is replaced with incorrect nucleotide and replace it.
correct nucleotide by the DNA polymerase and This is called mismatch repair. Together, these two systems
reduce the number of base mismatch errors to about one in one
sealed by DNA ligase.
billion. But DNA can get damaged after replication, too.
- Different Base pairs: Adenine, Guanine, Thymine,
Lots of different molecules can cause chemical changes to
Cytosine
nucleotides.
➢ Nucleotide repair Some of these come from environmental exposure, like certain
o ATP-dependent nuclease recognized the compounds in tobacco smoke. But others are molecules that
distorted double helix → excises the damaged are found in cells naturally, like hydrogen peroxide.
DNA nucleotide →excised section is restored Certain chemical changes are so common
by insertion of nucleotides into the gap by DNA that they have specific enzymes assigned to reverse the
polymerase and sealed in placed by DNA damage.
ligase. But the cell also has more general repair pathways.
If just one base is damaged, it can usually be fixed by a process
❖ Recombinational Repair called base excision repair. One enzyme snips out the damaged
- Usually occurs when excision repair fails to occur base, and other enzymes come in to trim around the site and
replace the nucleotides. UV light can cause damage that's a little
before DNA replication begins.
harder to fix. Sometimes, it causes two adjacent nucleotides to
- The polymerase that enable to initiate their
stick together, distorting the DNA's double helix shape.
function of polymerizing a daughter strand. Damage like this requires a more complex process
- Recombination – the different strands from called nucleotide excision repair. A team of proteins removes a
different parent will combine → the resulting long strand of 24 or so nucleotides, and replaces them with
daughter have the characteristic of both male and fresh ones. Very high frequency radiation, like gamma rays and
female parent. x-rays, cause a different kind of damage.
- DNA recombination damage → DNA strand that They can actually sever one or both strands of the DNA
is not damaged is being crossed over with the backbone.
damage DNA strand. Double strand breaks are the most dangerous. Even one can
- It will remove the cross over damage strand and cause cell death.
replaced by another strand. The two most common pathways for repairing double strand
➢ Results in two homologous but dissimilar DNA breaks are called homologous recombination and non-
homologous end joining.
duplexes. – since coming from different parent.
Homologous recombination uses an undamaged section of functions of loss neurons → they cannot be
similar DNA as a template. Enzymes interlace the damaged and regenerated.
undamaged strands, get them to exchange sequences of
nucleotides, and finally fill in the missing gaps to end up with ▪ Tissue Repair
two complete double-stranded segments. Non-homologous end - Since tissues are made up of cells → these cells
joining, on the other hand, doesn't rely on a template. are capable of multiplying.
Instead, a series of proteins trims off a few nucleotides and then
- Damage is usually reversed by apoptosis or
fuses the broken ends back together. This process isn't as
necrosis of the injured cells → regeneration of the
accurate. It can cause genes to get mixed up, or moved around.
But it's useful when sister DNA isn't available. Of course, tissues by proliferation.
changes to DNA aren't always bad. Beneficial mutations can • Apoptosis
allow a species to evolve. But most of the time, we want DNA to - It has a full value of repair for tissues that are
stay the same. Defects in DNA repair are associated with made up of constantly renewing cell.
premature aging and many kinds of cancer. So if you're looking - Such as bone marrow, respiratory, GI epithelium
for a fountain of youth, it's already operating in your cells, and epidermis of the skin.
billions and billions of times a day. - For continuously dividing cells such as hepatic
and renal parenchymal cells.
▪ Cellular Repair - But, the apoptosis is ineffective with non-
• Repair of damaged neurons replicating and non-replaceable cells such as
- Peripheral neurons with axonal damage are repaired neuron, cardiac cells and female germ cells.
by macrophages and Schwann cells - Causes cell to shrink as its nuclear and cytoplasmic
- Schwann cells are a type of glial cells of the materials condense, and then breaks into
peripheral nervous system. membrane-bound fragments that are phagocytosed
- It helps form our myelin sheath around the without inflammation
nerve fibers. - Also intercept the process leading to a neoplasia
- It surrounds our neurons., and they are well (multiplication of cancer cells) by eliminating the
protected. cells with potentially mutagenic DNA damage.
- It usually envelops and rotates around the axon
forming myelin sheath. → myelinated – • Proliferation: Regeneration of Tissue
nakasurround sa kanya ang schwann cells. - The repaired injured tissues will involve both
- Faster communication and faster transfer of regeneration of lost cells and extracellular matrix
neurons. and reintegration of the newly formed elements
- Without myelin sheath, there can be a to tissues and organs.
mismatch of communication or transfer of - The regeneration of tissue will be promoted by
information. the replacement of cells by mitosis.
- Macrophages usually remove the debris in the - Replacement of cells by Mitosis
process of phagocytosis and by production of ➢ Intracellular signaling is turned on and expression
cytokines. of numerous genes is increased.
- These cytokines are secreted by a specific cells - Ex: Transcription factors in which it
of the immune system such as the stimulates other genes that gives product
macrophages. that regulate the cell division cycle.
- It can mediate and regulate our immunity. - Replacement of the Extracellular Matrix
- Cytokines are the first defenses of our immune ➢ Composed of proteins, glycosaminoglycans, and
system and it will counteract the antigen or the glycoprotein and proteoglycans
foreign materials inside our body as a result it ➢ Stimulated by the TGF-beta
will cause inflammation and hematopoiesis in
the body. • Side Reactions to Tissue Injury
- Macrophages produces our growth factors - Inflammations
which then activates the Schwann cells to - Lesions may be associated with fever and
proliferate. inflammations.
- Since damage to our CNS is reversible, there are - Therefore, the body is working for you. There
a large number of reserved nerve cells that can is a repair attempts in the body.
partly compensate by taking over the functions - Usually the resident macrophages and
of neurons. endothelial cells are activated by cell injury
- Our nervous system has reserve nerve cells. → then produce the inflammation, fever, and the
if damage there will be a replacement of the altered production of the proteins.
➢ Cells and Mediators - If you have adaptation in the toxicity, it may result to
▪ Initiated by resident macrophages secreting biological changes causing;
cytokines such as TNF-alpha and IL-1 in 1. diminished delivery of the toxicant to the target
response to damage → stimulates the 2. decreased size or susceptibility of the target
stromal cells to release mediators that induce 3. increased capacity of the organism to repair itself
dilation of local microvasculature and cause 4. strengthened mechanisms to compensate the toxicant-
permeabilization of capillaries. inflicted dysfunction.
▪ Endothelial cell facilitates the egress
(facilitates the moving out) of circulating - Ex. In a certain community, there is someone who
leukocytes into the injured cells. releases toxicants, one family totally had a reaction
with the toxicant but another family had no effect or
➢ Inflammation produces Reactive oxygen and any changes on them
nitrogen species RONS - The one family who didn’t have any changes → have
▪ Macrophages and leukocytes in the ste of the mechanism of adaptation.
injury undergoes respiratory burst that - Adaptation involves sensing the harmful chemicals and
produces free radicals and activated enzymes the initial damage or dysfunction and their response
- These produced free radicals are due to typically occurs during the altered gene expression.
the membrane-bound NADPH oxidase - Aside from their genetics in adapting the toxicant, there
that is activated. are also chemicals that can induce adaptive changes,
- Although free radicals possesses as a result;
antimicrobial activity at the site of o lessen delivery by diminishing the absorption
microbial invasion, it can also damage o increasing the removal by intracellular binding
the healthy tissues adjacent to the protein
injured ones also. o enhancing their detoxification
o promoting cellular export
- Altered Protein Synthesis: Acute-phase Proteins - Chemicals are dose related – smaller exposure then it
➢ IL-6, IL-1, and TNF increase or decrease the will not incure any damages.
transcriptional activity of genes encoding certain
proteins – positive and negative acute – phase
proteins.
- IL-6, IL-1, and TNF are activated by
macrophages and the endothelial cells at the
site of injury.
- Positive – role is to minimize tissue injury
and facilitates repair.
- Negative – role is on toxication and
detoxification of xenobiotics and the
disposition and toxicity of chemical may be
altered also.
- Generalized reactions
➢ May evoke neurohormonal responses
- Production of IL-1, TNF, IL-6 → can alter the
temperature that is set point of hypothalamus
triggering fever.
- Also act in the pituitary to induce the release
of ACPH → this will stimulate the secretion of
cortisol from the adrenals and inhibit the
cytokine gene expressions.
Mechanisms of Adaptation
- Responses acting to preserve or regain the biological
homeostasis in the phase of increase harm from the
harmful stimulus or toxicants.
STEP 4- Repair or Dysrepair
- There are instances why the body cannot initiate repair.
- If the body fails to repair damage, it will overwhelm repair mechanisms as necessary
enzymes and cofactors are consumed.
- Sometimes, toxicants adversely affect the repair process itself.
- Dysrepair
- Occurs at molecular, cellular, and tissue levels.
- Some toxicities can occur at a specific enzyme or processes such as; tissue
necrosis, fibrosis, and chemical carcinogenesis (cancer).
● Toxicity Resulting from Dysrepair
○ Tissue Necrosis
■ Occurs when molecular repair mechanisms are inefficient or molecular
damage is irreversible
● NOTE: Tissue necrosis is dose concentration dependent, meaning
a high dose of toxicant can cause a degree of damage that will
compromise repair, allowing the progression to injury.
■ Dose-concentration dependent that leads to the disable of repair
mechanism, including (1) repair of damaged molecules, (2) elimination of
damaged cells by apoptosis, (3) replacement of lost cells by cell division
■ Apoptosis and cell proliferation can halt the progression of injury to
necrosis
● Especially if the damaged cells are the ones proliferated. It can
stop the progression of necrosis.
● Cell proliferation through the process of mitosis.
○ Fibrosis
- A pathologic condition that is characterized by excessive deposition of the
extracellular matrix of abnormal composition, thus producing a remodeled tissue.
- The abnormal/mutated composition of the extracellular matrix.
- When you put the extracellular matrix to the site of repair, it can change
the target molecule/site. This leads to the development of fibrous
connective tissue as a reparative response to injury or damage.
- EXAMPLE: Our body will find a way to compensate for the damage/loss.
So, our body will try to produce and adapt to the loss of composition or
molecules. Even if our body has healed, our body will still produce that
extracellular matrix, so much that it can produce mutated compositions.
■ Develops when Increased production of extracellular matrix is not halted
● Our body will try to increase more production even if it is not
needed anymore.
■ TGF-Beta is the major mediator of the fibrogenesis
● TGF is stimulated when there is injury and it continues to
proliferate until repair is complete.
○ Carcinogenesis
■ Failure of DNA repair
● Results to mutation of Proto-oncogenes and Tumor-suppressor
genes
○ Mutation of Proto-oncogenes
■ It happens when there is an overexpression or
permanent activation of the different proteins
produced which leads to neoplastic transformation.
■ Responsible for the stimulating progression of cells
in the cell cycle, produces growth factors and signal
transducers.
○ Mutation of Tumor-suppressor genes
■ Leads to the activation of the PF or p53 protein
which arrests or stops the cell cycle which leads to
apoptosis.
■ Suppressor genes inhibit the progression of cells in
the cycle.
○ Therefore, the accumulation of the genetic damage in the
form of Proto-oncogenes and Tumor-suppressor genes will
allow for the transformation of the normal cells with
controlled proliferative activity to malignant cells with
uncontrolled proliferative activity, thus affecting/altering the
balance of mitosis and apoptosis.
■ Initiation cells/Initiated cells initiate cancer. It is
mutated and is in the first stage of cancer cell
development. Cancer cells will undergo mitosis and
will become malignant until the boomerang effect
happens and spreads throughout the body.
■ Failure of Apoptosis
● Promotes clonal expansion of initiated cells and tumor cells which
induce tumor regression
● Initiated cells are normal cells before that are changed/mutated so
that they are able to form tumors or cancer cells.
■ Failure to Terminate Proliferation
● Increase mitotic activity also increases the probability of mutations
● Overproduced proto-oncogene facilitates the neoplastic
transformation of cells
● When cell-to-cell communication is disrupted during proliferation it
contributes to the invasiveness of tumor cells
ABSORPTION, DISTRIBUTION, BIOTRANSFORMATION, AND ELIMINATION
- The mechanism of toxicity and the disposition of chemical or xenobiotics is defined as
the composite action of its ABSORPTION, DISTRIBUTION, BIOTRANSFORMATION,
AND ELIMINATION. This disposition is actually a quantitative disposition known as
“toxicokinetics” which involves toxic agents.
Factors affecting disposition

1. If the fraction absorbed or the rate of absorption is low, a chemical may never attain a
sufficiently high concentration at a potential site of action to cause toxicity.
2. The distribution of a toxicant may be such that it is concentrated in a tissue other than
the target organ, thus decreasing toxicity.
3. Biotransformation of a chemical may result in the formation of less toxic or more toxic
metabolites at a fast or slow rate with obvious consequences for the concentration and
thus the toxicity at the target site.
4. The more rapidly a chemical is eliminated from an organism, the lower will be its
concentration and hence its toxicity in target tissues.
EXAMPLES:
- If the patient has diarrhea. Diarrhea means fast motility. Fast motility also speeds up the
movement of chemicals, therefore lowering its concentration onto the target organ/site.
- If the chemical is distributed to or stored in a fat, its elimination is likely to be slow
because very low levels preclude the rapid renal clearances or other renal clearances. In
other words, if the toxic agents are lipids and the elimination is slow, then it has the
possibility to accumulate in the body therefore causing more toxicity.
Absorption
● Absorption is the process by which the toxicant will cross the body membranes and enter
the bloodstream.
● The transfer of a chemical from the site of exposure, usually an external or internal body
surface, into the systemic circulation
● GI tract, lungs and skin
● Substance requirements and factors that increases the rate of absorption:
○ Lipid soluble
○ Unionized
○ Diluted
○ Molecular size
■ Reduced size will also increase the surface area, therefore increasing the
absorption process.
○ Concentration
○ Dissolution rate
- Same as toxic agents.
Absorption of Toxicants by the GI tract
- Usually the toxicant is either an organic acid or base. They are absorbed by
simple/passive diffusion. From the region of high to low concentration and does not
involve any carriers and does not require energy. Lipid soluble substances can readily
move across most biological membranes due to their solubility in the membrane bilayers,
such as the Gi tract, because they are surrounded by fats.
- The Gi tract is mostly lipid form, so absorption of toxicant is fast.
● The GI tract has at least one active transport system that decreases the absorption
system that decreases the absorption of xenobiotics. (mdr-p-glycoprotein)
○ Mdr-p-glycoprotein decreases the absorption of xenobiotics. It is a form of
transport system in the GI tract.
ABBREVIATION NAME FUNCTION
Active transporters (ABC

family)
mdr1/P-gp Multidrug-resistant Efflux from gut, brain, and

protein/P-glycoprotein placenta; biliary excretion
● Biliary excretion is
a reversible transfer
of toxicant or toxic
metabolites from
the plasma to bile
through
hepatocytes,
usually followed by
the intestinal
reabsorption of the
toxicant/toxin.
bsep Bile salt export pump Bile salt transport
mrp Multidrug Multidrug resistance in

resistance-associated many tissues,
protein organic-anion efflux,
glucuronide, and
glutathione conjugates,
nucleoside transport
BCRP Breast cancer resistance Organic anion efflux,

protein mainly sulfate conjugates
oatp Organic-anion transporting Transport of organic

polypeptide anions, cations, and
neutral compounds
(sodium independent)
oat Organic-anion transporter Transport of organic
anions, predominantly in
kidney
oct Organic-cation transporter Transport of organic

cations, predominantly in
kidney and liver
pept Peptide transporter Transport of di- and

tripeptides, some
xenobiotics
● The residency time of chemical in the intestine depends on intestinal motility

- The faster the gastric emptying, the faster the absorption, therefore the rate of
absorption of the toxicant remaining for longer periods in the intestines will increase,
whereas shorter residency will decrease.
○ Factors:
■ 1. Lipid water solubility
■ 2. Molecule size
■ 3. Particle size
■ 4. Degree of ionization
■ 5. Physical forms
■ 6. Chemical nature
■ 7. Dosage forms
■ 8. Formulation
■ 9. Concentration
● The amount of chemical entering the systemic circulation after oral administration
depends on the amount absorbed into the GI cells, biotransformation by the GI cells, and
extraction by the liver into bile.
○ First pass effect or presystemic elimination or the removal of chemicals before
entering systemic circulation.
○ Usually, the drug or toxicant that is absorbed from the Gi tract will pass via the
portal vein into the liver where some drugs are metabolized.
○ Sometimes, the result of the first pass metabolism means only a portion of the
toxicant reaches the circulation, therefore decreasing the toxicity of toxicant or
toxic agents.
Absorption of Toxicants by the Lungs

● Toxicants absorbed by the lungs are usually gases, vapors of volatile or volatizable
liquids and aerosols.
○ Usually, the absorption via lungs is the second fastest administration.
● Aerosol and Particles
- Usually the major characteristics that can affect the absorption after exposure to
aerosols are the aerosol size and the water solubility of the chemical present in the
aerosol.
- The smaller the particle of the aerosol, the farther into the respiratory tree the particle will
deposit.
● Gases and Vapors
- Usually highly reactive gases.
- EXAMPLES: Gasoline, kerosene, rugby/solvent.
○ When a gas is inhaled into the lungs, gas molecules diffuse from alveolar space
into the blood and then dissolve until gas molecules in the blood are in
equilibrium with gas molecules in the alveolar space.
■ Usually, the blood carries the dissolved gas molecules to the rest of the
body and then in each tissue, gas molecules are transferred from the
blood to the tissue until equilibrium is reached.
■ The ratio of the concentration of the chemical in the blood and chemical in
the gas phase is constant.
Absorption of Toxicant through the Skin

- NOTE: For a chemical to be absorbed through the skin, the toxicant must pass through
the epidermis or the appendages (7 cell layers) such as the sweat, sebaceous glands,
and hair follicles. Usually, slower absorption through the skin is slower because it needs
to pass several layers unless the skin is damaged such as cuts, scratches, or burns then
absorption is fast.
● Chemicals that are absorbed through the skin have to pass through seven cell layers
before entering the blood and lymph capillaries in the dermis.
○ All toxicants will move across the stratum corneum by passive diffusion.
○ Usually polar substances appear to diffuse through the outer surface of the
potent filaments by the hydrated stratum corneum, while non polar molecules will
dissolve in and diffuse through the lipid matrix between the filaments.
● One of the factors that affects the permeability of the skin will depend on the diffusibility
and the thickness of the skin.
○ If the skin is also hydrated, the faster the absorption.
● Percutaneous absorption
- The diffusion of toxicants will follow from;

- Epidermis
- Stratum granulosum
- Spinosum
- Germinativum
- Dermis
- Then to Systemic circulation.
● FACTORS:
1. Compromised stratum corneum integrity
2. Increased stratum corneum hydration
a. Same principles as bandages, hydration = increased absorption.
3. increased temperature, which increases dermal blood flow
4. Low solubility of the toxicant in the vehicle
5. Small size
Absorption of Toxicants after Special Routes

● Interaperitoneal , subcutaneous, intramuscular, intravenous
○ Intraperitoneal
■ Results in rapid absorption of xenobiotics because of the rich blood
supply and the largely relative surface area of the peritoneal cavity.
■ Usually absorbed primarily through portal circulation and therefore must
pass through the liver before reaching other organs by the way of
systemic circulation.
○ Subcutaneous and
○ Intramuscular
■ Usually, administered toxicants are absorbed at lower rates but it can
enter directly into general circulation.
○ Intravenous
■ Faster, direct to the veins.
Distribution
- The rate of distribution to the organs or tissues is usually determined primarily by blood
flow and the rate of diffusion out of the capillary bed into the cells of the particular organ
or tissue.
- Therefore, blood flow is the determinant.
- NOTE: Always consider different distribution disturbances especially if the patient
has cardiovascular or vessel diseases, or perfusion disorders which is the
passage of fluid through the circulatory system or lymphatic system to an organ
or a tissue.
- The final distribution also depends largely on the affinity of xenobiotics for various
tissues.
● Factors:
1. Capillary permeability
2. Degree of the binding of the toxicants to the plasma and tissue proteins
3. Relative hydrophobicity of the toxicant
- In order to know if the substance or xenobiotics is well distributed, usually the vd is
determined, the volume in which the amount of toxicant would need to be uniformly
dissolved in order to produce the observed blood concentration.
- Also consider the plasma protein binding; bound and unbound.
- If the xenobiotics are more bound to plasma protein then less volume distribution,
therefore prolonging the half life within the body and will affect the dose threshold
of toxicity. Toxicants will take a long time to eliminate but it will not reach its target
site.
● The concentration of a toxicant in blood depends largely on its volume of distribution
(vd).
● Water compartments in the body
1. Plasma compartment
● If it has a very large molecular weight and it can bind extensively in plasma
proteins, therefore it can be trapped within the plasma or vascular compartments.
2. Extracellular fluid
● Composed of plasma and interstitial fluid.
● If the xenobiotics have low molecular weight and are hydrophilic, therefore they
can move through the endothelial slit junction of the capillaries into the interstitial
fluid.
3. Total body water-
● If the xenobiotics has low molecular weight and is hydrophobic.
4. Other sites
● May include the fetus.
○ Fetus may take up drugs, therefore will increase the volume of
distribution.
Biotransformation
- Is the sum of all the chemical processes of the body that can modify endogenous or
exogenous chemicals. In other words, this is the chemical elimination of substances.
- To change the structure of substances into more hydrophilic ready for the
excretion process.
- Liver is the major site of biotransformation, because of the high concentration of
enzymes such as the cyp450. Biotransformation mostly happens in the liver.
- Biotransformation can also happen in the lungs, stomach, intestines, skin, and
kidneys.
- All the substances will be converted from hydrophobic to hydrophilic which will aid to the
faster elimination/excretion. Substances become polar and water soluble.
● Results of biotransformation:
○ Increase toxicity via a toxic metabolite
○ Decrease toxicity via metabolism of a toxic parent compound
○ No effect on toxicity
○ Present to metabolize endogenous compounds
● Major Categories/Reaction
○ Phase 1
■ AKA the Functional group modification.
■ There is an addition of a functional group so that the xenobiotics become
polar which is ready for elimination.
■ Oxidation: Cytochrome P-450, MFO, alcohol, dehydrogenase, oxidases,
others
● The most important reaction in Phase 1.
● Adding of oxygen and removal of hydrogen, therefore increases
the valence of the compound.
■ Reduction: Reductases
● Less important.
● Removal of oxygen and adding of more hydrogen which result in
decreased valence.
■ Hydrolysis: esterases, phosphates, others.
● Splitting compounds by adding water.
○ Phase 2: glucuronic acid, glutathione, sulfate, acetyl group, methyl group
■ AKA the Conjugation phase.
■ Increases the molecular size and makes the substance more polar for
excretion.
Excretion
● Toxicants are removed from the systemic circulation by biotransformation, excretion, and
storage at various sites in the body.
● Removal of xenobiotics from the blood and returned to the external environment via
urine, feces, and exhalation.
● May also happen in saliva, sweat, breast milk, hairs, skin, and even the cerebrospinal
fluid. But the main excretion happens via urine, feces, and exhalation. Saliva, sweat,
breast milk, hairs, skin, and cerebrospinal fluid are rare.
● When the rate of absorption exceeds the rate of elimination, then toxic compounds may
accumulate which then reaches a critical concentration at the target site and eventually
more toxicity may occur.

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PHARMACEUTICAL TOXICOLOGY MT | TERM

Professors: Stephanie Lois Sanchez

What is Toxicology? § Hippocrates (circa 400 B.C)

• Shape of the Dose-response curve

Variations in Toxic Responses

• Margins of Safety and Exposure

STEP 2 - REACTION OF THE ULTIMATE TOXICANT WITH THE

STEP 3 – CELLULAR DYSFUNCTION AND RESULTANT

STEP 3 - CELLULAR DYSFUNCTION AND RESULTANT

• Nicotine acts as an activator for Acetylcholine nicotinic

Step 4 - Repair or Dysrepair

• Step 4 - Repair or Dysrepair

• Step 4 - Repair or Dysrepair

Factors affecting disposition

ABBREVIATION NAME FUNCTION

Active transporters (ABC

mdr1/P-gp Multidrug-resistant Efflux from gut, brain, and

bsep Bile salt export pump Bile salt transport

mrp Multidrug Multidrug resistance in

BCRP Breast cancer resistance Organic anion efflux,

oatp Organic-anion transporting Transport of organic

oct Organic-cation transporter Transport of organic

pept Peptide transporter Transport of di- and

● The residency time of chemical in the intestine depends on intestinal motility

Absorption of Toxicants by the Lungs

Absorption of Toxicant through the Skin

- The diffusion of toxicants will follow from;

Absorption of Toxicants after Special Routes

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