Oxidation - Oxidation Reactions Are Some of The Most Common Xenobiotic Transformations Occurring in

BMFT/168J/2020
KIPNGETICH DIEGO
Assignment
Toxicology
1.Using examples explain the oxidation reactions of xenobiotics
Oxidation - Oxidation reactions are some of the most common xenobiotic transformations occurring in

plants.
These Phase I reactions result in either detoxication or activation of the herbicide. Many of these

oxidative reactions are presumed to be catalyzed by cytochrome P-450 monooxygenases.
Monoxygenases catalyze reactions in which one of the two atoms of molecular oxygen is incorporated
into the substrate (e.g. herbicide or xenobiotic) and the atom is reduced to water by an electron donor,
such as NADPH
An example of an oxidation reaction is the hydroxylation of amphetamine to 4-hydroxyamphetamine

and norephedrine. Another example is hydroxylation of delta-9-THC to 11-OH-delta-9-THC. The enzymes
of oxidation include mixed-function oxidases, monoxygenases, and cytochrome P450 enzymes.
Arachidonic acid is metabolized via the epoxidation and omega-hydroxylation to many biologically active
eicosanoids such as epoxyeicosatrienoic acids and hydroxyeicosatetraenoic acids by multiple P450
isoforms including CYP2C, CYP2E1 and CYP4A11. CYP2D in the brain may be involved in the metabolism
of neuronal amines and steroids and in the regulation of the central nervous system. CYP1A2 and
CYP3A4 appear to be the major P450 enzymes catalyzing the oxidation of all-trans-retinol to all-trans-
retinoic acid in human liver, and CYP3A4 is one of the vitamin D3 25-hydroxylases.
2.using examples explain the dealkylation reactions of xenobiotics
O-dealkylation:
It is accepted that P450 catalyzed O-dealkylation reactions proceed by the two-step hydrogen atom
abstraction/oxygen rebound mechanism similar to aliphatic hydroxylations. In the first step, the enzyme
removes a hydrogen atom from the carbon adjacent to the oxygen (Hydrogen atom transfer, HAT), to
generate a neutral carbon radical. Hydroxyl recombination follows in the second step to form a
hemiacetal intermediate. The hemiacetal then dissociates non-enzymatically to an alcohol and a
carbonyl compound. This mechanism is supported by large kinetic deuterium isotope effects (kH/kD = 8–
10) measured during O-dealkylation reactions which were in the same range for P450 catalyzed aliphatic
hydroxylations and chemical models. Also loss or inversion of stereochemical configuration supports a
two step mechanism.
N-Dealkylation is a frequently encountered metabolic reaction. It is often responsible for the production

of the major metabolite obtained from an N-alkyl containing drug. Its prominence does not simply
derive from the commonality of an alkyl-substituted amino group as an important part of the structural
motif of many drugs. It arises primarily as a consequence of N-dealkylation being energetically
favored.10 Typical examples include the N-demethylation of methamphetamine , the N-deethylation of
lidocaine, and the N-deisopropylation of propranolol , to form the secondary amines 21, 23, and 25,
respectively.
3.Using examples explain the aromatic hydroxylation reactions of xenobiotics.
The cytochromes P450 hydroxylate arenes as a means of detoxification in the body. The activation of

aromatic substrates by P450 enzymes generates several products, including phenols, arene oxides, and
ketons.
Experimental studies concluded that arene oxides are intermediates in the reaction leading to phenol
products. Hydroxylation at aromatic carbon atoms proceeds through stepwise oxygen transfer, More
recent studies on selectively deuterated mono-substituted benzenes as well as
various epoxides provided strong evidence for a stepwise mechanism rather than the initially proposed
pathways that proceeded entirely through symmetrical arene oxide intermediates [27]. As shown
for phenytoin, there is an initial attack of FeO3+ on the aromatic system to form a tetrahedral carbon
intermediate, followed by oxygen rebound with electron transfer and release of metabolites. The
resulting products may include mono-hydroxylated aromatics, as well as arene oxides formed from the
same tetrahedral intermediate. For example, the major metabolite of phenytoin formed by CYP2C9 is 4-
hydroxyphenytoin, which is then excreted in urine after glucuronide conjugation. The 4-hydroxy- and 3-
hydroxyphenytoins are further metabolized by CYPs to 3,4 dihydroxyphenytoin, a catechol. The
phenytoin catechol also may be oxidized by peroxidases in skin to a reactive quinone, possibly a
causative agent for phenytoin idiosyncratic drug reactions.

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BMFT/168J/2020

1.Using examples explain the oxidation reactions of xenobiotics

Oxidation - Oxidation reactions are some of the most common xenobiotic transformations occurring in

These Phase I reactions result in either detoxication or activation of the herbicide. Many of these

An example of an oxidation reaction is the hydroxylation of amphetamine to 4-hydroxyamphetamine

2.using examples explain the dealkylation reactions of xenobiotics

N-Dealkylation is a frequently encountered metabolic reaction. It is often responsible for the production

3.Using examples explain the aromatic hydroxylation reactions of xenobiotics.

The cytochromes P450 hydroxylate arenes as a means of detoxification in the body. The activation of

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