Iranian

Iranian J Publ Health, Vol. 37, No.4, 2008, pp.1-18J Publ Health, Vol. 37, No.4, 2008, pp.1-18 Review Article

Glucose-6-phosphate dehydrogenase (G6PD) Deficiency

DD Farhud 1, *L Yazdanpanah 2
1
Genetic Clinic, Vallie Asr Sq, 16 Keshavarz Blvd. Tehran, Iran.
2
Dept.of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran

(Received 28 Apr 2008; accepted 3 Dec 2008)

Abstract
Glucose-6-phosphate dehydrogenase (G6PD) Deficiency is the most prevalent enzymopathy in mankind. It has sex-linked
inheritance. This enzyme exists in all cells. G6PD deficiency increases the sensitivity of red blood cells to oxidative dam-
age. G6PD deficiency was discovered in 1950 when some people suffered hemolytic anemia as a result of taking antimalar-
ial drugs (primaquin). Most people with G6PD deficiency do not have any symptoms, till they are exposed to certain medi-
cations, Fava beans and infections; and then their red blood cells are hemolyzed. The degree of hemolysis changes accord-
ing to the degree of enzyme deficiency and the oxidant agent exposure. G6PD deficiency has many different variants and
Mediterranean variant is the most common mutation in the world. G6PD deficiency is considered a health problem world-
wide, especially in Asia, Middle East and Mediterranean countries. In this article, we have reviewed the importance and
function of G6PD enzyme, incidence rate of G6PD deficiency in the world and Iran, genetic and variants of this enzyme,
clinical manifestation, diagnosis and treatment of the enzyme deficiency.

Keywords: G6PD, Oxidative damage, Sex-linked inheritance, Hemolytic anemia, Mediterranean variant

Introduction in the enzyme deficiency. Neonatal screening and

Glucose-6-phosphatase dehydrogenase (G-6-PD) health education can reduce the incidence rate
deficiency is the most common enzymopathy in of G6PD deficiency clinical manifestations (1).
humans (1). G6PD deficiency was discovered for The goal of this article is to review the importance
the first time when hemolytic anemia occurred of G6PD enzyme in antioxidant defense enzyme
in some persons who consumed anti-malarial drug system, function of the enzyme, prevalence of
named primaquine (1, 2). It is an X-linked dis- G6PD deficiency in the worldwide, structure and
order and is a highly polymorphic enzyme. This different mutations of this enzyme, The major cli-
enzymopathy affects 400 million people world- nical manifestations like acute hemolytic anemia
wide (3). The enzyme gene is located on the long induced by oxidative drugs and some infections,
arm of the X- chromosome (Xq28) (1). neonatal jaundice and chronic non-spherocytic he-
G6PD catalyzes the first step of pentose phos- molytic anemia, diagnosis and treatment of the en-
phate pathway, during this reaction NADPH is zyme deficiency.
produced and protects red blood cells from Importance of G6PD Enzyme
oxidative damage (4-6). Super oxide, hydrogen peroxide, hydroxyl radical
Most deficient people do not show any symp- is called ROS (Reactive Oxygen Species). They
toms until following exposure to oxidative drugs, cause oxidative stress and damage cell’s Mem-
some infections and ingestion of Fava bean (1). branes (7, 8).
Mediterranean mutation is the most common vari- Increased production of ROS or decreased anti-
ant of enzyme deficiency and often associated oxidant defense enzymes play a major role in oxi-
with favism (2, 3). dative injuries in different organs, tissues and cells
Avoiding of the oxidative agents that induces he- including brain, heart, vascular cells (8) and ca-
molytic anemia is the most important treatment uses brain diseases like Alzheimer and Parkin-

*Corresponding author: Tel: +98 912 3681025, E-mail: [email protected] 1

 DD Farhud and L Yazdanpanah: Glucose-6-phosphate…

son diseases and also considered to contribute In these samples, activities of superoxide dismuta-
to the aging process (9-11). se, Catalase, Glutathione peroxidase and G6PD
Enzymes like superoxide dismutases, catalase, glu- in red blood cells were measured. They showed
tathione peroxidases, glutathione reductase and that activities of this enzyme in patients were sig-
glucose-6-phosphate dehydrogenase are antioxi- nificantly lower than normal person. These find-
dant defense enzymes. In body defense anti-oxi- ings demonstrated that oxidative stress is the main
dant system, G6PD is considered as an essential cause of the start and progress of neurodegen-
modulator enzyme that has a very important role erative in the patients and can also be related
in all cells especially in red blood cells (8). with intensity of the disease (14).
To know the crucial role of G6PD, at first the Function of G6PD
role of other anti-oxidant enzymes must be un- G6PD catalyzes the first step in the pentose phos-
derstood. Superoxide dismutase converts two su- phate pathway, converts Glucose-6-phosphate into
per oxide radicals into one hydrogen peroxide 6-phosphogluconolactone and during this conver-
and one oxygen (8). Catalase converts hydrogen sion, the important reductant metabolite named
peroxide into water and oxygen (8, 12). Gluta- NADPH is provided. The pathway is the only
thione peroxidase is necessary for reducing hy- source for producing of NADPH in red blood
drogen peroxide and lipid peroxides to water cells (2), because they lack mithochondria, nu-
and lipid alcohols (8). Glutathione reductase: main cleus and ribosomes and other pathways that
role of this enzyme is regenerating reduced glu- produce NADPH(4). NADPH is necessary for
tathione (GSH) from oxidized form (GSSG) (8, 12). generating of GSH from its oxidized form, GSSG,
G6PD is a key enzyme for maintenance of re- and subsequent maintenance of intracellular GSH
dox potential in cells. G6PD produces NADPH in pools. GSH maintains normal structure, elastic-
pentose phosphate pathway. NADPH is impor- ity and integrity of red blood cells, and sustain
tant as a central reductant and regulates of re- hemoglobin in ferrous state that is essential for
dox potential (13). It also acts as a cofactor for carrying oxygen (4). G6PD and NADPH are key
other anti-oxidant enzymes like glutathione reduc- factors for protection of red blood cells from
tase (8, 12). oxidative damage and peroxides (2). Peroxides
Reduced glutathione is required as a cofactor for are usually removed from red blood cells by
the glutathione peroxidases and, thus reduced glu- glutathione peroxidase that uses reduced glu-
tathione and glutathione cycles is crucial for neu- tathione. Reduced glutathione reacts with harm-
tralization of hydrogen peroxide and lipid per- ful peroxides and neutralize them. In this reac-
oxides and also protects protein sulfhydryl groups tion reduced glutathione is oxidized and gluta-
against oxidation (2). thione reductase regenerates reduced glutathione
Catalase is found in two forms, active and inac- by using of NADPH. NADPH is oxidized and
tive, NADPH is critical for conversion of inac- G6PD is required for producing reduced NADPH
tive form into active form (2). again (1, 2).
Different studies point out the importance of
G6PD enzyme in other cell functions like its con-
trol of cell death. G6PD is a principal enzyme in
cell death and intracellular redox potential needs
to be regulated to control cell death (13). As the
production of ROS increases, so does cell death.
In another study, role of anti-oxidant enzyme and
oxidative stress in Parkinson disease was sur-
veyed. One hundred and fifteen patients with
Parkinson and 37 healthy people were selected.

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 Iranian J Publ Health, Vol. 37, No.4, 2008, pp.1-18

Fig. 1: Function of G6PD (5)

Catalase is another anti-oxidant enzyme that is ants. It is postulated that the high frequency of
abundant in red blood cells and helps to the re- G6PD deficiency has arisen because G6PD de-
moval of peroxides from red blood cells through ficient variants confer some resistance against se-
activation by NADPH (2). Unless peroxides are vere malaria caused by Plasmodium falciparum
neutralized, they will cause oxidative injuries. He- (4, 15, 16). The exact mechanism of this protec-
moglobin and red blood cell membrane molecules tion is still unknown. Red blood cells are the host
that contain SH groups are destroyed (1, 2). cells for Plasmodium falciparum. Plasmodium
Hemoglobin is denatured irreversibly, precipitates parasites oxidize NADPH and diminish the level
and forms Heinz bodies. Heinz bodies destroy of reduced glutathione (GSH) in red blood cells.
membranes of red blood cells then leads to hae- This effect in G6PD deficiency is more severe,
molysis and acute anemia. leading to oxidative-induced damage to the RBC
Regarding to the roles of NADPH in redox state (4). Also Plasmodium parasites break down he-
of cells, G6PD is the principal enzyme in chain moglobin, and release toxic substances like Fe,
reaction that is necessary for protecting all cells which is a source of oxidative stress and it will
especially red blood cells against oxidant agents cause hemolysis (17). Therefore the growth of
(2). Then G6PD-deficient cells especially red Plasmodium parasites is decreased. In addition,
blood cells are susceptible to damage by reac- damaged red blood cells are removed by phago-
tive oxygen species and oxidative stress (2). cytosis at an early ring-stage of parasites’ matu-
Malaria and G6PD deficiency ration, and that decreases the growth of parasites
The geographical distribution of malaria is similar even more (1, 18).
to the world distribution of deficient G6PD vari-

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 DD Farhud and L Yazdanpanah: Glucose-6-phosphate…

Farhud et al. performed a study in the north of zyme, bind one of the phosphates in NADP (2).
Iran. They measured serum proteins and immu- The shift between two active forms depends on
noglobulins in favic patients and healthy controls, PH. Aggregation of inactive monomers and con-
both school boys. The results showed higher version into an active form requires presence of
amounts in healthy individuals and normal range NADPH (2, 24).
in patients. The normal range in the patients is Variants of G6PD
suggested to be due to positive selection that in- According to the level of enzyme activity, World
duces a developed immune response and pro- Health Organization classified variants of G6PD
duces better chances not to get affected by some to five groups (15, 25).
other endemic infectious diseases such as ma- Class 1: Severe deficiency of the enzyme with
laria (19). Chronic nonspherocytic hemolytic anemia.
Genetics, structure Class 2: Severe deficiency of the enzyme, en-
The gene for the G6PD enzyme is one of the zyme activity is less than 10% of normal.
important genes located on the telomeric region Class 3: Moderate deficiency of the enzyme, en-
of the long arm of X chromosome (Xq28) (1, 5, zyme activity is %10-60 of normal.
20), are more likely to affect males than females. Class 4: Very mild to none deficiency of the en-
Males are more likely than females to suffer all X- zyme, enzyme activity is %60-100 of normal.
linked genetic conditions, such as G6PD deficiency Class 5: There is increased enzyme activity.
(21). Mutations that are responsible for class 1 variants
Clinical and biochemical analyses have character- are confined to the NADP binding site of the en-
ized more than 400 (2, 22) variants most emerg- zyme or glucose-6-phosphate binding site (2, 24).
ing from point mutations in the coding region They are located near the carboxy end of the en-
of gene (2, 23), base changes that result in amino zyme (25). They form severe clinical symptoms
acid substitution, displaying a field of pheno- because they are clustered at the position invo-
types with different abnormal enzyme activity lved in the dimmer formation of the active form
and wide ranging degree of clinical symptoms of G6PD (26, 27) and influence stability and
(23). Monomer of G6PD has 515 amino acids activity of enzyme (27). But mutations that cause
with a molecular weight 59 kDa (2, 24). mild clinical symptoms are located at the amino
G6PD in the active form consists of the same sub- end of the molecule (25). G6PD variants that have
units of either dimmer or tetramer and includes been discussed in this article are shown in Table 1.
tightly bound NADP (2, 24). It is supposed that G6PD variants that have been characterized at
Lys and Arg, amino acids 386 and 387 in en- the DNA level are shown in Table 2.

Table 1: G6PD variants that have been discussed in this article (2)

Biochemical variants Nucleotide substitution Amino acid substitution WHO class

A- 202G A 68Val Met 3

376A G 126Asn Asp
Mediterranean 563C T 188Ser Phe 2
Mahidol 487G A 163Gly Ser 3
Viangchan 871G A 291Val Met 2
Cosenza 1376G C 459Arg Pro 2
Chatham 1003G A 335Ala Thr 3

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 Iranian J Publ Health, Vol. 37, No.4, 2008, pp.1-18

Table 2: G6PD variants that have been characterized at the DNA level (2)

Variant Nucleotide Substitution WHO Class Amino Acid Substitution

Gaohe 95 A G 2 32 His Arg

Gaozhou
Sunderland 105-107 del 1 35 Ile del
Aures 143 T C 2 48 Ile Thr
Metaponto 172 G A 3 58 Asp Asn
A-
Distrito Federal
Metera
Castilla 202 G A 3 68 Val Met
Alabama 376 A G 126 Asn Asp
Betica
Tepic
Ferrara
Ube 241 C T 3 81 Arg Cys
Konan
Lagosanto 242 G A 3 81 Arg His
Vancouver 317 C G 1 106 Ser Cys
544 C T 182 Arg Trp
592 C T 198 Arg Cys
Sao Borga 337 G A 4 113 Asp Asn
A 376 A G 4 126 Asn Asp
Chinese- 4 392 G T ? 131 Gly Val
Ilesha 466 G A 3 156 Glu Lys
Mahidol 487 G A 3 163 Gly Ser
Plymouth 488 G A 1 163 Gly Asp
Chinese-3 493 A G 2 165 Asn Asp
Shinshu 527 A G 1 176 Asp Gly
Santamaria 542 A T 2 181 Asp Val
376 A G 126 Asn Asp
Mediterranean
Dallas
Birmingham 563 C T 2 188 Ser Phe
Sassari
Cagliari
Panama
Coimbra 592 C T 2 198 Arg Cys
Santiago 593 G C 1 198 Arg Pro
Sibari 634 A G 3 212 Met Val
Minnesota
Marion 637 G T 1 212 Val Leu
Gastonia
Harilaou 648 T G 1 216 Phe Leu
Mexico City 680 G A 3 227 Arg Gln
A- 680 G T 3 227 Arg Leu
376 A G 126 Asn Asp
Stonybrook 724-729 1 242-243
GGC del Gly & Thr
Wayne 769 G C 1 257 Arg Gly
Cleveland 820 G A 1 274 Glu Lys
Chinese-1 835 A T 2 279 Thr Ser

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 DD Farhud and L Yazdanpanah: Glucose-6-phosphate…

Table 2: Continued…
Variant Nucleotide Substitution WHO Class Amino Acid Substitution

Seattle
Lodi 844 G C 2 282 Asp His
Modena
Lodi 844 G C 2 282 Asp His
Modena
Montalbano 854 G A 3 285 Arg His
Viangchan 871 G A 2 291 Val Met
Jammu
West Virginia 910 G T 1 303 Val Phe
Kalyam 949 G A 3 317 Glu Lys
Kerala
A- 968 T C 3 323 Leu Pro
Betica 376 A G 126 Asn Asp
Seima
Nara 953-976 del 1 319-326 del
Chatham 1003 G A 3 335 Ala Thr
Fushan 1004 C A 2 335 Ala Asp
Chinese-5 1024 C T ? 342 Leu Phe
Irepetra 1057 C T 2 353 Pro Ser
Loma Linda 1089 C A 1 363 Asn Lys
Olomouc 1141 T C 1 381 Phe Leu
Tomah 1153 T C 1 385 Cys Arg
Iowa
Walter Reed 1156 A G 1 386 Lys Glu
Iowa City
Springfield
Guadalajara 1159 C T 1 387 Arg Cys
Mt. Sinai 1159 C T 1 387 Arg Cys
376 A G 126 Asn Asp
Beverly Hills
Genova 1160 G A 1 387 Arg His
Worcester
Praba 1166 A G 1 389 Glu Gly
Nashvill
Anaheim 1178 G A 1 393 Arg His
Calgary
Portici
Alhambra 1180 G C 1 394 Val Leu
Puetro Limon 1192 G A 1 398 Glu Lys
Riverside 1228 G T 1 410 Gly Cys
Japan 1229 G A 1 410 Gly Asp
Shinagava
Alhambra 1180 G C 1 394 Val Leu
Puetro Limon 1192 G A 1 398 Glu Lys
Riverside 1228 G T 1 410 Gly Cys
Japan 1229 G A 1 410 Gly Asp
Shinagava
Alhambra 1180 G C 1 394 Val Leu
Puetro Limon 1192 G A 1 398 Glu Lys
Riverside 1228 G T 1 410 Gly Cys

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 Iranian J Publ Health, Vol. 37, No.4, 2008, pp.1-18

Table 2: Continued…

Variant Nucleotide Substitution WHO Class Amino Acid Substitution

Alhambra 1180 G C 1 394 Val Leu
Puetro Limon 1192 G A 1 398 Glu Lys
Riverside 1228 G T 1 410 Gly Cys
Japan 1229 G A 1 410 Gly Asp
Shinagava
Tokyo 1246 G A 1 416 Glu Lys
Georgio 1284 C A 1 428 Tyr End
3/ interon
Varnsdorf 1 N/A
10 splice site del
Pawnee 1316 G C 2 439 Arg Pro
Telti 1318 C T 1
440 Leu Phe
Kobe
Santiago de Cuba 1339 G A 1 447 Gly Arg
Cassano 1347 G C 2 449 Gln His
Union
1360 C T 2 454 Arg Cys
Maewo
Andalus 1361 G A 1 454 Arg His
Cosenza 1376 G C 2 459 Arg Pro
Taiwan-Hakka 2
1376 G T 459 Arg Leu
Gifu-like
Kaiping 1388 G A 463 Arg His
2
Anant
Dhon
Petrich
Sapporo
Campinas 1463 G T 1 488 Gly Val

G6PD deficiency in the World are detected in Kuwaiti population. Postulating

Based on the findings of WHO, 7.5% of the world that gene flow from the Indian Sub-continent,
populations have one or two genes for G6PD de- sub-Saharan Africa and other parts of Mediter-
ficiency and 2.9% are G6PD deficient (28). ranean is responsible for molecular heterogenity
The best known G6PD-deficient variants that oc- of G6PD variants in the population (30, 32). The
cur at a high frequency are G6PD A- and the Me- most G6PD variant in Italy, Sardinia and Greece
diterranean variants. Mediterranean mutations are is G6PD Mediterranean.
identified by very low activity in red blood cells In Egypt and Libya, North of Africa, G6PD Me-
(29). Mediterranean variant is the most com- diterranean is the most common variant (30).
mon variant in Southern Europe, Middle East, G6PD A- and G6PD Mediterranean have re-
and India (2). Rate of incidence of Mediterra- spectively the highest rate of incidence in Alge-
nean mutation in Turkey is (77%), Iran (69%), ria and both of them are associated with Fav-
India (60.4%), and also in Pakistan (30) and ism. Molecular heterogenous G6PD deficiency
Saudi Arabia the Mediterranean mutation is the in Algeria suggests gene flow from Sub-Saharan
prevalent variant (31). Africa and other parts of Mediterranean (33).
In Kuwaiti population, the most common variants G6PD A- is found in Africa, Southern Europe and
are G6PD A- and the Mediterranean variants and all areas African people were taken to (2). G6PD
also a lower rate of Chatham variant and Aures deficiency in Spain is heterogenous. The most

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 DD Farhud and L Yazdanpanah: Glucose-6-phosphate…

prevalent variant in Spain is G6PD A-. Two other angchan, Mahidol and canton were the most pre-
important variants are Seattle and Union. The ex- valent G6PD variants in Thais. G6PD Viangchan
istence of G6PD Aures and Santamaria, that are in Laotians and non-Chinese Southeast Asian po-
polymorphic in Algeria, suggests significant gene pulation is probably the most common variant (37).
migration from Africa to Europe through Spain G6PD deficiency in IRAN
(30, 34). The prevalence of G6PD deficiency in Iranian po-
G6PD deficiency in Mexico is heterogenous and pulation is 10-14.9% reported by WHO (28).
G6PD A- is relatively prevalent. Prevalence of The most prevalent variant of G6PD deficiency in
G6PD A- and Seattle mutations in Mexico were Iran is the Mediterranean (38-40), and the next
likely introduced by African slaves and Spanish most prevalent variant is Chatham, and Chat-
immigrants (35). ham incidence rate is 13-27% (39).
Viangchan, Mediterranean and Mahidol are com- The incidence rates of G6PD mutations in dif-
mon G6PD mutations in the Malays (36). Vi- ferent provinces in Iran are shown in Table 3.

Table 3: The Prevalence of G6PD mutations in provinces of Iran (38, 40)

Khorasan Mazandaran Golestan Hormozgan Sistan and Gilan kermanshah

Balochestan

Percent of Medit 66 69 62.2 79.45 80.42 86.4 91.2

mutation

Percent of 12 27 26.8 8.21 2.17 9.7 7.3

Chatham
mutation

The incidence rate of G6PD deficiency in Tehran larities to those in Khorasan neighboring such
neonates was 2.1% (41). In a study in Kerman- as Afghanistan and Turkmenistan (30).
shah Province 5.3% of samples were severely Clinical Manifestations of G6PD deficiency
deficient in G6PD enzyme. Polymorphic muta- Acute hemolytic anemia, neonatal jaundice and
tions in the region were Mediterranean, Chat- chronic non spherocytic hemolytic anemia are the
ham, Cosenza (40). There are higher prevalence major clinical manifestations associated with G6PD
of G6PD deficiency in northern and southeast- deficiency that discussed in this article:
ern provinces of Iran (8.6- 16.4% in Northern
provinces, 12% in southern part [Shiraz] and 1. Acute hemolytic anemia
19.3% in southeastern of Iran) (42, 43-45). a. induced by oxidative drugs
The three mutations found in the three northern b. Favism
provinces of Iran were Mediterranean, Chatham, c. Infection-induced hemolysis
Cosenza (42). Khalili et al reported the preva- 2. Chronic non spherocytic hemolytic anemia
lence of G6PD deficiency in Gilan, a northern 3. Neonatal jaundice
province of Iran 6.4% (46). In Khorasan, North-
eastern province of Iran, 22% of samples did not 1. Acute hemolytic anemia
display one of the known mutations in Iran. Dif- Unless exposed to oxidative agents like oxidative
ferent ethnic groups who are living in this prov- drugs, infections and ingestion of fava beans,
ince include Persian, Turkmen, Afghan, Turk, Kurd most patients with G6PD deficiency show no
and Arab. The unknown variants of enzyme de- sign of acute hemolytic anemia (1, 4). Hemolytic
ficiency observed in the region may bear simi- anemia in G6PD A- is self-limited because in this

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 Iranian J Publ Health, Vol. 37, No.4, 2008, pp.1-18

mutation the younger red blood cells contain injuries that cause hemolysis (47, 51). Drugs,
normal G6PD enzyme activity. But in Mediter- substances and herbs can induce hemolytic ane-
ranean G6PD with severe enzyme deficiency, he- mia in G6PD deficient people are shown in tables
molytic anemia is not self-limited. All red blood 4, 5.
cells have enzyme deficiency and don’t resist in Primaquine
hemolysis (2, 15, 47). People with G6PD deficiency are about 20 to 30
a. Induced by oxidative drugs times more sensitive to the hemolytic activity of pri-
Each person’s response to specific drugs is af- maquine than the people with normal G6PD (52).
fected by genetic variations in an enzyme or en- Mechanism for induction of hemolytic anemia
zyme system (48). Adverse drug reactions (ADRs) was studied in rats (52, 53). Toxic metabolites of
are a significant cause of morbidity and mortal- primaquin cause reduction of GSH in red blood
ity. Acute hemolytic anemia induced by anti-ma- cells (53), formation of methemoglobin (51) and
larial drugs is an example of adverse drug reac- Heinz bodies that induce hemolytic anemia (52,
tions that had been recognized for long time in 53). The primaquine metabolite, 6-methoxy-8-hy-
G6PD deficient people. In these people, due to droxylaminoquinoline after N-hydroxylation from
a defect in the gene coding for G6PD, the activ- 6-methoxy-8-aminoquinoline (52), by peroxida-
ity of the enzyme is reduced and that caused tion of lipids in red blood cells with significant
this adverse effect (49). Pharmacogenetics was in- GSH and oxidation of protein in GSH-depleted
troduced by Vogel in 1959 for study the re- red blood cells can induce hemolytic response
lationship between genetic variations in genes in- (52).
volved in drug metabolism and drug response. Henna
More recently, the term pharmacogenomics has Henna is a cosmetic dye that is used for dying
also been introduced, that is the broader appli- hair, nails (54, 55) and also for treatment der-
cation of genomic technologies and considers the matitis (56). Some studies identified that henna
genetic variants, patterns of gene expression and can induce hemolytic anemia (55, 57, 58). Law-
the way drugs influence gene function. It is pos- sone (2-hydroxy-1,4-naphthoquinone) is a che-
tulated that pharmacogenomics is the study of mical substance in henna, and its structure and re-
entire genome, meanwhile pharmacogenetics is dox potential is similar to naphthalene metabolites
the study of a single gene. The term pharma- that induce oxidative damage in red blood cells
cogenomics can be used to cover both Pharma- especially in G6PD-deficient person (55).
cogenetics and Pharmacogenomics. Pharmacoge- Tea and Polyphenols
nomics offers major potential benefits by im- In a study in China effects of extracts of black
proving drug response, reducing ADRs and un- tea, green tea and decaffeinated green tea and
derstanding disease susceptibility (50). their polyphenols on G6PD-deficient red blood
Some drugs cause oxidative stress and induce he- cell in vitro were examined. The results showed
molysis in G6PD-deficient red blood cells. They that extracts of tea and their two polyphenol (epi-
form hydrogen peroxide when they come in con- gallocatechin-3-gallate and epigallocatechin) cha-
tact with hemoglobin (47). nged oxidative condition in G6PD- deficient red
During this reaction reduced glutathione is oxi- blood cells in vitro. Level of GSH is lowered; me-
dized rapidly, glutathione pools are exhausted, themoglobin, hemoglobin and GSSG are raised.
hemoglobin is denatured and Heinz bodies are The observed changes depend to doses of tea ex-
formed (2, 47). Red blood cells with enzyme de- tracts and polyphenols that are used. These cha-
ficiency are not capable of reducing NADP to nges are not observed in normal red blood cells
NADPH for regenerating reduced glutathione from (59).
oxidized form that is necessary for inactivating
peroxides and protecting cells against oxidative

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 DD Farhud and L Yazdanpanah: Glucose-6-phosphate…

Table 4: Drugs and substances should be avoided by G6PD deficient individuals (1, 2, 60).
Drugs and substances (group) Examples
Anti malarial drugs Primaquin
Sulphonamides Sulphacetamid, Sulphametoxazole, Sulphanilamid, Sulphapyridin
Sulphones Thiazolesulfone, Dapsone
Other sulphur-containing drugs Glibenclamide
Nitrofurans Nitrofurantoin(Furadantin)
Other drugs Toluidin blue, Trinitrotoluene(TNT), Urate oxidase, Phenylhydrazine, Furazolidone (Furoxone),
Methylene Blue, Nalidixic acid, Niridazole, Phenazopyridine, Isobutyl Nitrite, Acetanilide, Aspirin
Cosmetic substance Henna
Other substances Naphthalene, Moth balls, High-dose of vitamin K or ascorbic acid
Food substance Fava beans

Table 5: Drugs and Substances (with their molecular formulation) should be avoided by G6PD deficient individuals
according to the G6PD Deficiency Association (61)

Name Molecular Forumla Risk Levels Population at risk

Acetanilide (acetanilid) C8 H9 N O High Medit., Asian
Acetylphenylhydrazine (2-Phynylacetohydrazide) C8 H10 N2 O High All
Aldesulfone sodium (sulfoxone) C14 H14 N2 Na2 O6 S3 High All
Aminophenazone (aminopyrine) C13 H17 N3 O Low All
Antazoline (antistine) C17 H19 N3 Low All
Arsine As-H3 High All
Ascorbic Acid C6 H8 O6 Low All
Beta-Naphthol (2-Naphthol) C10 H8 O High All
Chloramphenicol C11 H12 C12 N2 O5 High Medit., Asian
Chloroquine C18 H26 Cl N3 High Medit., Asian
Ciprofloxacin C17 H18 F N3 O3 High Medit., Asian
Colchicine C22 H25 N O6 Low All
Dapsone (diaphenylsulfone) C12 H12 N2 O2 S High All
Dimercaprol C3 H8 O S2 High All
Diphenhydramine (difenilhydramine) C17 H21 N O Low All
Dopamine (L-dopa) C8 H11 N O2 Low All
Doxorubicin C27 H29 N O11 High Medit., Asian
Furazolidone C8 H7 N3 O5 High All
Glibenclamide C32 H28 Cl N3 O5 S High Medit., Asian
Glucosulfone (glucosulfone sodium) C24 H34 N2 Na2 O18 S3 High All
Isobutyl Nitrite C4 H9 N O2 High Medit., Asian
Isoniazid C6 H7 N3 O Low All
Menadiol Sodium Sulfate (Vitamin k4 sodium sulfate) C11 H8 Na2 O8 S2 High All
Menadione (menaphtone) C11 H8 O2 High All
Menadione sodium Bisulfite (Vitamin K3 sodium bisulfite) C11 H8 O2 NaHSO3 High All
Mepacrine (Quinacrine) C23 H3O Cl N3 O High Medit., Asian
Mesalazine-5-Aminosalicylic Acid(paraminosalicylic acid) C7 H7 N O3 High Medit., Asian
Methyltioninium Chloride (methylene blue) C16 H18 Cl N3 S High All
Nalidixic Acid C12 H12 N2 O3 High Medit., Asian
Naphtalene, Pure (naphtalin) C10 H8 High All
Niridazole C6 H6 N4 O3 S High All
Nitrofural (nitrofurazone) C6 H6 N4 O4 High All
Nitrofurantoin C8 H6 N4 O5 High All
Norfloxacin C16 H18 F N3 O3 Low All
O-Acetylsalicylic Acid (acetylsalicylic acid) C9 H8 O4 High Medit., Asian

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 Iranian J Publ Health, Vol. 37, No.4, 2008, pp.1-18

Table 5: Continued…

Name Molcular Formula Risk Levels Population at Risk

O-Acetylsalicylic Acid (acetylsalicylic acid) C9 H8 O4 High Medit., Asian

Oxidase, Urate (urate oxidase) ____________ High Medit., Asian
Pamaquine C42 H45 N3 O7 High All
Para-Aminobenzoic Acid (4-Aminobenzoic Acid) C7 H7 N O2 Low All
Paracetamol (acetaminophen) C8 H9 N O2 Low All
Pentaquine C18 H27 N3 O High All
Phenacetin (acetophenetidin) C10 H13 N O2 High Medit., Asian
Phenazone (antipyrine) C11 H12 N2 O Low All
Phenazopyridine C11 H11 N5 High Medit., Asian
Phenylbutazone C19 H20 N2 O2 Low All
Phenytoin C19 H20 N2 O2 Low All
Phynylhydrazine C6 H8 N2 High All
Phytomenadione (Vitamin K1) C31 H46 O2 Low All
Primaquine C15 H21 N3 O High All
Probenecid C13 H19 NO4 S High All
Procainamide C13 H21 N3 O Low All
Proguanil (chlorguanidine) C11 H16 Cl N5 Low All
Pyrimethamine C12 H13 Cl N4 Low All
Quinidine C20 H24 N2 O2 Low All
Quinine C20 H24 N2 O2 Low All
Stibophen (2-(2-Oxido-3,5-Disulphonatophenoxy)- C12 H4 Na5 O16 S4 Sb High All
1,3,2,Benzodioxastibole-4-6-Disulphonate)
Streptomycin C21 H39 N7 O12 Low All
Sulfacetamide C8 H10 N2 O3 S High All
Sulfacytine C12 H14 N4 O3 S Low All
Sulfadiazine C10 H10 N4 O2 S Low All
Sulfadimidine C12 H14 N4 O2 S High All
Sulfafurazole (sulfafurazone, sulfisoxazole) C11 H13 N3 O3 S High Medit., Asian
Sulfaguanidine C7 H10 N4 O2 S Low All
Sulfamerazine C11 H12 N4 O2 S Low All
Sulfamethoxazole C10 H11 N3 O3 S High All
Sulfanilamide (Sulphanilamide) C6 H8 N2 O2 S High All
Sulfapyridine C11 H11 N3 O2 S High All
Sulfasalazine, Salazosulfapyridine (salazopyrin) C18 H14 N4 O5 S High All
Thiazosulfone (thiazolesulfone) C9 H9 N3 O2 S2 High Medit., Asian
Tiaprofenic Acid C14 H12 O3 S Low All
Tolonium Chloride, Tolonium Chloride (toluidine C15 H16 Cl N3 S High All
blue)
Trihexyphynidyl (benzhexol) C20 H31 N O Low All
Trimethoprim C14 H18 N4 O3 Low All
Trinitrotoluene (2,4,6-Trinitrotoluene) C7 H5 N3 O6 High Medit., Asian
Tripelennamine C16 H21 N3 Low Medit., Asian

Food substances and herbs that should be avoided by G6PD deficient people
Fava Beans
Some prefer also to avoid red wine, all legumes, blueberries (also with yogurt), soya products, tonic water.
Chinese Herbs to Avoid: Cattle Gallstone Bezoar (Bos Taurus Domesticus), Honeysuckle (Lonicera Japonica),
Chimonanthus Flower(Chimonanthus Praecox), Huang Lian (黄连), 100% Pearl Powder

11
 DD Farhud and L Yazdanpanah: Glucose-6-phosphate…

b. Favism tive oxygen species that induce oxidative stress to

Favism is hemolytic anemia which occurs after the the erythrocytes, and will damage them and will
ingestion of fava beans especially fresh fava beans cause hemolysis (1, 2).
in G6PD-deficient individual and that’s why the 2. Chronic non spherocytic hemolytic anemia
highest incidence rate of favism is at the time of Some of the rare variants of G6PD deficiency
harvest (1, 2, 15, 62). which are designated as class 1 variants, accord-
Favism is always observed in people with G6PD ing to the classification of WHO, are associated
deficiency, but all G6PD-deficient people do not with Chronic non spherocytic hemolytic anemia
develop hemolysis. Therefore, G6PD deficiency (1, 2, 26).
is an essential factor for the occurrence of favism Individuals in this class have very low enzyme ac-
but it is not enough (2, 15). Most cases of favism tivity (26) and suffer from hemolytic anemia even
are observed in Mediterranean type of G6PD- when oxidative agents are not present (2). They
deficient because the level of enzyme activity is very are variably anemic in steady state condition (1, 2).
low and deficiency is severe, and occasionally in Splenomegaly is commonly present. The disorder
individuals with G6PD A- variant (1, 2). is usually identified during infancy and childhood
Clinical symptoms of favism are pallor, jaundice, (15).
hematuri and acute hemolytic anemia occurs 24- 3. Neonatal jaundice
48 h after consumption of fava beans, suddenly Serum bilirubin levels are determined by produ-
(1, 15, 63). Ahaptoglobinemia was found in fav- ction of bilirubin, bilirubin conjugation and elimi-
ism patients (64, 65). There is a low haptoglo- nation. Hyperbilirubinemia is caused by the im-
bin serum in G6PD deficient individuals. Hap- balance between the rate of production of bilir-
toglobin is a serum protein of the alpha-2 frac- ubin, the end product of heme metabolism, and
tion, binds to free hemoglobin whenever intravas- restricted excretion of bilirubin in newborns (70,
cular hemolysis occurs, the complex cleared by 71). The average total serum bilirubin level is
phagocytes and then haptoglobin disappeared usually 5-6 mg per dl (86-103 µmol per l) in
from plasma (65, 66). full term newborns (71). Hyperbilirubinemia oc-
Vicine and convicine are pyrimidine glucoside curs due to either physiologic or pathologic causes
that are abundant in fava beans and make up 6.7 (71). Physiologic jaundice occurs when the se-
g/100 g of dry weight of fava beans (67). These rum total bilirubin is in a range of 7 to 17 mg
substances are metabolized by B-glucosidase in per dl (104-291 µmol per l). A total serum bilir-
body to divicine and isoramil that are unstable ubin level higher than 17 mg per dL is consid-
aglycons, and are oxidized rapidly and form hy- ered pathologic hyperbilirubinemia. One of the
drogen peroxide and superoxide anion. These me- common risk factors for pathologic hyperbilirubi-
tabolites oxidize reduced glutathione in normal nemia in newborn infants is deficiency of G6PD
and G6PD-deficient red blood cells (67-69). De- enzyme (71). Deficiency of this enzyme is the
pletion of reduced glutathione and impairment of most prevalent enzymopathy in red blood cells
some important enzyme induce oxidative stress that causes hemolysis and hyperbilirubinemia (72).
in G6PD-deficient red blood cells and lead to Hyperbilirubinemia can be very severe in G6PD-
acute hemolytic anemia called favism (2, 68, 69). deficiency and induces permanent damage to the
c. Infection-induced hemolysis brain and causes kernicterus and death (72). Over-
The most common cause of hemolysis is possi- production of unconjugated bilirubin and lack of
bly the infection in G6PD-deficient individuals proper management of hyperbilirubinemia cause
(1, 2). Viral, bacterial and rickettsial infections, changes in the mitochondria of the basal ganglia
especially hepatitis, pneumonia and typhoid fever and leads to impaired mitochondrial respiration,
induce hemolysis in G6PD- deficient people (1). and also induce apoptosis, and cause bilirubin
During phagocytosis, leukocytes may release ac- encephalopathy (73).

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 Iranian J Publ Health, Vol. 37, No.4, 2008, pp.1-18

The pathogenesis of hyperbilirubinemia in G6PD- By using the Quantitative spectrophotometric me-

deficient newborn babies is different from that in thod, activity of G6PD Enzyme was determined
G6PD-normal ones. Meanwhile hemolysis is con- by measuring the rate of the reduction of NADP to
sidered to be a principal cause of bilirubinemia NADPH in the presence of G6P and hemolysate
in G6PD-normal neonates; but diminished bilir- (15, 76). Another Screening method for G6PD
ubin conjugation would be the main cause of hy- deficiency is dichlorophenol-indophenol (DPIP)dye
perbilirubinemia in G6PD-deficient newborn in- decolorization. This method is used for determin-
fants (70). Profile of serum bilirubin in newborns ing of G6PD in red blood cells. By this method
with G6PD-deficiency showed that the amount of hetrozygotes are diagnosed easily and is used
total and unconjugated bilirubin is high and con- when a large number of population are screened
jugated bilirubin is low. These levels of different for determination of G6PD deficiency (15).
forms of bilirubin that are seen in the neonates Laboratory tests and clinical features in patients
are similar in conditions of partial deficiency of with G6PD deficiency and hemolysis are: Hemo-
the bilirubin conjugating enzyme UDP glucurono- globinuria, Increased indirect bilirubin, Elavated se-
syltransferase, such as Gilberts syndrome. High rum lactate dehydrogenase,
levels of unconjugated bilirubin in G6PD-deficient Low serum haptoglobin (up to ahaptoglobinemia),
neonates are the result of an interaction between Complete blood count (CBC), elevated reticulo-
G-6-PD deficiency and variant promoter for the cyte count, Heinz bodies are presented on pe-
gene encoding this enzyme, UDP glucuronosyl- ripheral blood smear, Comb's test (the test in he-
transferase (74). molysis phase is negative) (77, 78).
Although there is a natural immaturity of bilir- Treatment
ubin conjugationin in neonates, the bilirubin con- The main treatment for G6PD deficiency is avoid-
jugation ability of G6PD-deficient neonates who ance of oxidative agents like infection, fava beans
are also heperbilirubinemic is even less efficient. and oxidative drugs that induce hemolysis (1, 4).
Bilirubin conjugation ability in G6PD-deficient neo- Hemolysis may be so severe that it may even re-
nates may become worse due to increased hemo- quire blood transfusion (2). Screening of new-
lysis and more bilirubin production (70, 74). borns for early diagnosis of G6PD deficiency and
Diagnosis proper education can reduce the incidence of cli-
Beutler fluorescent spot test, dichlorophenol indo- nical symptoms (1). These methods have been
phenol decolourization and quantitative spectro- successfully applied in northern Sardinia and the
photometric assey are methods used for the di- result was that the incidence of Favism has be-
agnosis of G6PD deficiency (15, 75). Beutler fluo- come less and also in Singapore kernicterus in the
rescent spot test is the most acceptable method neonates is now very rare. Proper control and early
for screening of G6PD deficiency (76). During treatment in neonatal jaundice are very impor-
this method, the rate of NADPH production from tant (1). Phototherapy is used to decrease bilir-
NADP by G6PD is measured under ultraviolet ubin concentration and when the bilirubin levels
light (15, 66). G6PD non-deficient blood samples exceeds 20 mg/dl, exchange transfusion is nec-
fluoresce brightly, but deficient samples show essary (2). In regions that G6PD deficiency is pre-
little or no fluorescence (75-77). valent, there is a grave danger of giving G6PD-
When individuals are actively hemolyzing, the deficient blood to such newborns and this has to
test can show normal results wrongly, because be prevented (1). Using desferrioxamine could
sustaining younger erythrocytes show normal en- make the attacks of Favism less severe. Use of
zyme activity or near normal. Thus the indivi- Sn-mesoporphyrin (SnMP) that inhibits heme ox-
duals should be screened several weeks after a ygenase and decreases bilirubin production in
hemolytic episode (15, 75). G6PD-deficient neonates has decreased the need

13
 DD Farhud and L Yazdanpanah: Glucose-6-phosphate…

for phototherapy and exchange transfusion (1, 79, 4. Prchal JT, Gregg XT (2005). Red Cell En-
80). Because of some adverse effects of Sn- zymes. Hematol, 1: 19-23.
mesoporphyrin, SnMP should only be used for 5. Greene LS (1993). Deficiency as Protection
neonates who are in a clear danger of developing Against falciparum Malaria: An Epide-
bilirubin-induced neurologic dysfunction or those miological Critique of Population and Ex-
who are taking part in clinical trials (79). In clini- primental Studies. Yearbook of Phys
cal experiments, use of antioxidants like vitamin Anthropol, 36: 153-78.
E and selenium have not shown any benefit for 6. Jain M, Brenner DA, Cui L, Lim CC, Wang
the treatment of G6PD deficiency (1). B, Pimentel DR, et al. (2003). Glucose-
Conclusion 6-Phosphate Dehydrogenase Modulator
G6PD deficiency is one of the most common Cytosolic Redox Status and Contractile
X-link inherited hemolytic disorders reported, af- Phenotype in Adult Cardiomyocytes. Circ
fecting around 400 million people worldwide. The Res, 93: e9.
main function of G6PD is to protect the RBC 7. Shihabi A, Li WG, Miller FJ, Weintraub
against oxidative damage. The most important way NL (2002). Antioxidant therapy for ath-
for prevention and reduction in the incidence rate erosclerotic vascular disease: the prom-
of clinical symptoms of G6PD deficiency is to ise and the pitfalls. Am J Physiol Heart
avoid oxidative agents like infection, fava beans Circ Physiol, 282: H797-H802.
and oxidative drugs that induce hemolysis, also 8. Leopold JA, Loscalzo J (2005). Oxidative
screening of newborns for early diagnosis of Enzymopathies and Vascular Disease. Ar-
G6PD deficiency and proper education is rec- terioscler Thromb Vasc Biol, 25:1332.
ommended. 9. Tsun-Yee Chiu D, Liu TZ (1997). Free radi-
cals and oxidative damage in human blood
cells. J Biochem Sci, 4: 256-59.
Acknowledgements
10. Halliwell B (1992). Reactive Oxygen Spe-
The authors are both thankful to Prof A Jazayery,
cies and the Central Nervous System. J
School of Public Health, and Dr H Sadighi,
Neurochem, 59 (5), 1609-23.
Genetic Clinic, for reading the manuscript and
11. Savitha S, Tamilselvan J, Anusuyadevi M,
giving some suggestions.
Panneerselvam C (2005). Oxidative stress
This study was supported partly by Iran TWAS
on mitochondrial antioxidant defense sys-
chapter based at ISMO in Tehran.
tem in the aging process: role of DL-alpha-
The authors declare that they have no conflict
lipoic acid and L-carnitine. Clin Chim Acta,
of interests.
355: 173-80.
12. Fico A, Paglialunga F, Cigliano L, Abrescia
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Neonates: A Determining Factor in the

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