We all are exposed through air, food, drinks and skin contacts to harmful compounds throughout the period of our lifetime, including, a variety of pharmaceuticals and food-derived carcinogen metabolite (e.g. N-acetoxy-PhIP), , plant toxins (such as - Plants like potatoes, tomatoes, peppers, egg plant, tobacco, some spices. - Chemical compounds foreign to the human organism without nutritional value - A group of mycotoxins of which aflatoxin B1 is the most potent hepatocarcinogen - A toxin producing by cyanobacteria of which microcystin-LR is predominant
- Plants like potatoes, tomatoes, peppers, egg plant, tobacco, some spices.
- Chemical compounds foreign to the human organism without nutritional value
- A group of mycotoxins of which aflatoxin B1 is the most potent hepatocarcinogen
- A toxin producing by cyanobacteria of which microcystin-LR is predominant
Biotransformation has been conveniently categorized into three distinct phases, which act in a tightly integrated manner. Phases I and II enzymes catalyze the conversion of a lipophilic, non-polar xenobiotic into a more water-soluble and therefore less toxic metabolite, which can then be more easily excreted from the body. Phase I biotransformation seems to be enzymes that catalyzes oxidation, reduction or hydrolyze reactions, it usually converts substrates to more polar forms by introducing or unmasking a functional group (e.g., —OH, —NH2, or —SH). Phase I consist primarily of microsomal enzymes, which are found abundantly in the liver, gastrointestinal tract, lung and kidney, consisting of families and subfamilies of enzymes that are classified based on their amino acid sequence identities or similarities. . Many of the enzymes like monooxygenases are found in the endoplasmic reticulum membrane, but others such as the dehydrogenases for example alcohol dehydrogenases and peroxidases located in the cytoplasm, while still others such as monoamine oxidase are localized in mitochondria. Monooxygenases are also known as mixed function oxidases because in a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule: one oxygen atom appearing in the product and the other in a molecule of water. The reaction scope of monooxygenases includes heteroatom oxidation, aromatic and aliphatic hydroxylation, epoxidation, and Baeyer-Villiger oxidation. There are two major types of microsomal monooxygenase, both of which require NADPH as an external reductant: the cytochrome P450 (CYP) system and flavin-containing monooxygenases. The mechanism of CYP is a complex cascade of individual steps involving the interaction of protein redox partners and consumption of reducing equivalents, usually in the form of NADPH. The iron heme containing enzyme, CYP, consists of two enzymes: NADPH–cytochrome P450 reductase and CYP. It is involved in the oxidative metabolism of many endogenous substances such as steroids and bile acids, as well as the detoxication of a wide variety of xenobiotics. It can oxidize AFB1 to several products. Only one of these, the 8,9-exo-epoxide, appears to be mutagenic and the others are detoxification products. P4503A4, which can both activate and detoxicate AFB1, is found in the liver and the small intestine. , . Flavincontaining monooxygenases catalyze an NADPH- and an oxygen-requiring oxidation of substances (primarily xenobiotics) bearing functional groups containing nitrogen, sulfur, or phosphorus. The properties of the CYPs electron transport systems have also been reported .
In detoxification pathway, a series of enzyme-catalyzed processes with broad specificities convert the toxic substances into less toxic metabolites by chemical reactions within the body. Although biotransformation reactions take place within cytoplasm and mitochondria but they mostly happen within endoplasmic reticulum (E.R). Cell types also differ in their biotransforming potential for example cells located near the major points of xenobiotic entry into the body such as liver, lung, and intestine possess greater concentrations of biotransforming enzymes than others .
Phase II conjugation reactions which generally act follow phase I activation consists of reactions in which metabolites containing appropriate functional groups are conjugated with substances such as glucuronate, glutamate, sulfate, reduced glutathione or uridine diphosphate (UDP)-glucuronic acid to finally discharge them through urine or bile. In general, conjugation dramatically improves solubility, which then promotes rapid excretion. Among the several types of conjugation reactions which are present in the body, including glucuronidation, sulfation, and glutathione and amino acid conjugation, glutathione which is catalyzed by glutathione S-transferases, is the major phase II reaction in many species . With the exception of acetylation, methylation and fatty acid conjugation, the strategy of phase II biotransformation is to convert a xenobiotic to a more hydrophilic form via the attachment of a chemical moiety which is ionizable at physiological pH. This metabolic transformation also results in reduced affinity of the compound for its cellular target. , .
In animals, elimination of the soluble compounds from cells and excretion of biotransformed molecules from the body referred to as phase III. It has been suggested that the phase III of detoxification system to be called antiporter activity. Antiporter activity is an important factor in the first pass metabolism of pharmaceuticals and other xenobiotics. The antiporter is an energy-dependent efflux pump, which pumps xenobiotics out of a cell, thereby decreasing the intracellular concentration of xenobiotics. In eukaryotic organisms, they are actively excreted or compartmentalized in the vacuole by ATP-dependent GS-X pumps , . Indeed, as the glutathionylated moiety is hydrophilic, the conjugate cannot usually simply re-diffuse back into the cell . Antiporter activity in the intestine appears to be co-regulated with intestinal phase I CYP3A4 enzyme. This observation suggests the antiporter may support and promote detoxification. Possibly, its function of pumping non-metabolized xenobiotics out of the cell and back into the intestinal lumen, may allow more opportunities for phase I activity to metabolize the xenobiotic before it is taken into circulation. Although, most literature on detoxification refers to liver enzymes, as the liver is the site of the majority of detoxification activity for both endogenous and exogenous compounds, however, the first contact the body with the majority of xenobiotics take places in the gastrointestinal tract. Intestinal mucosa possesses enzyme systems capable of various types of biotransformation of xenobiotics . Among the detoxification pathways, glutathione conjugation pathway is the prominent route of AFB1 inactivation in liver of mammalians. Depending on the availability of cellular GSH and the activation of glutathione S-transferase subclasses, detoxification of AFB1 is facilitated .
Glutathione is a ubiquitous thiol-containing isotripeptide (γ-glu-cys-gly, FW 307.3), consisting of glycine, glutamic acid and cysteine molecules which was first discovered by Sir Fredrick Gowland Hopkins in 1920s, synthesized de novo in mammalian cells (Figure 1). This water soluble antioxidant compound is an unusual peptide in that the peptide bond between the glutamate residue and the cysteine residue is formed with the γ-carboxylate group of the former rather than the α-carboxylate group. Today along with β-carotene, ascorbic acid (vitamin C), α-tocopherol (vitamin E) and flavonoids - Glutathione, reduced form
- Glutathione, reduced form
Moreover, the GSH/GSSG - Glutathione, oxidized state
- Glutathione, oxidized state
3. Glutathione S-transferase
3.1. Classification and structure
The superfamily of the glutathione transferases are divided into at least four major families of proteins, namely cytosolic or soluble GSTs, mitochondrial GSTs, microsomal GSTs and bacterial fosfomycin-resistance proteins , , . The cytosolic GSTs (cGSTs) have been subgrouped into numerous divergent classes on the basis of their chemical, physical and structural properties , . The mitochondrial GSTs, also known as kappa class GSTs, are soluble enzymes that have been characterized in eukaryotes . The third GST family comprises membrane-bound transferases called membrane-associated proteins involved in ecosanoid and glutathione metabolism, but these bear no similarity to soluble GSTs . Representatives of all three families are also present in prokaryotes but the fourth family is found exclusively in bacteria . The mammalian soluble GSTs are so far divided into eight classes based on their amino acid sequences including: Alpha (α), Kappa (κ), Mu (µ), Omega (ω), Pi (π), Sigma (σ), Theta (θ) and Zeta (ζ), , , , . GSTs are named using a letter corresponding to their class membership and Arabic numerals after the subunit composition (
3.2. Presence of GST in cells
3.2.1. Microbial GST
For a long time, GST enzymes from microbial sources were neglected and were not systematically studied. One of the reasons for this was the poor activity of microbial GSTs with CDNB - 1-chloro-2,4-dinitrobenzene
3.2.2. GSTs of fungi and yeasts
Until recently, relatively little was known about the presence and role of GST in fungi. However, expression of GST has been reported in some fungal species such as
3.2.3. Plant GSTs
Plant GSTs are a family of multifunctional enzymes involved in the intracellular detoxification of xenobiotics and toxic compounds produced endogenously , . Most of the enzymes are stress-inducible and play a role in the protection of plants from adverse effects of stresses. However, the activities of different GSTs have been detected and characterized in many plants, including maize, wheat, tobacco, soybean, barley, chickpea, peanut, sorghum, and sugarcane , , , .
3.2.4. Mammalian GST
The isoenzymes of glutathione transferase have been most widely studied in rat liver. Six basic transferases in rat liver liver have been characterized. In rabbit, GST catalyzes the conjugation of activated AFB1 with glutathione. In an experiment to assess the abilities of lung and liver GSTs to conjugate AFB1-8, 9-epoxide, it has been shown that alpha-class and mu-class GSTs are of similar importance in catalyzing the reaction in the lung. The human glutathione S-transferase, possess both enzymatic and non-enzymatic functions and are involved in many important cellular processes, such as, phase II metabolism, stress response, cell proliferation, apoptosis, oncogenesis, tumor progression and drug resistance. The nonenzymatic functions of GSTs involve their interactions with cellular proteins, such as, Jun N-terminal kinase,(JNK), tumor necrosis factor receptor-associated factor-2 (TRAF2), apoptosis-signal-regulating kinase 1 (ASK), serine/threonine kinases (PKA, PKC), and tissue transglutaminase 2 (TGM2), during which, either the interacting protein partner undergoes functional alteration or the GST protein itself is post-translationally modified and/or functionally altered , .
3.3. Different functions of GST
3.3.1. The metabolic function of GSTs
GSTs have been reported to involve in steroid metabolism by catalyzing the isomerization of ∆5-androstene-3, 17-dione to, ∆4-androstene-3, 17-dione, and biosynthesis of prostaglandins. GST M2-2 is a prostaglandin E synthase in the brain cortex  and rat GST A1-1 and GST A3-3 catalyze the reduction of PGH2 to PGF2. The isomerization reaction of PGF2 to PGD2 is also catalyzed by sigma class of GST. PGD2, PGE2 and PGF2 act as hormones that bind to G-protein coupled receptors which regulate other hormones and neurotransmittors. Prostaglandin D2 and E2 are unstable and will easily be converted to prostaglandin J2 and A2, respectively and their derivatives inhibit NFκB,  a family of transcription factors that regulate the transcription of genes important for inflammatory processes. There are interesting speculations that GSTs might block other anti-inflammatory pathways by catalyzing the conjugation of GST to PGJ2 , 
3.3.2. The ligandin function of GSTs
Because of exhibiting a ligand binding function, glutathione tranferases, have been known as ligandin, a function, which involves the noncovalent binding of nonsubstrate hydrophobic ligands such as heme, bilirubin, various steroids, and conceivably some lipophilic anticancer drugs as well. Although GSTs are generally viewed as playing a protective role in foreign compound metabolism, they can also catalyze reactions that lead to toxification. Examples include the GST dependent metabolism of 1,2-dibromoethane and related haloalkanes and probably also metabolism of the 6-thiopurine prodrug azathioprin , . Similarly, the cytotoxicity of the polypeptide antibiotic neocarzinostatin is greatly enhanced by thiols such as GSH, although in this case there is no apparent requirement for GST catalysis , . .
3.3.3. The regulatory function of GSTs
In addition to above functions, GSTs also are responsible for interacting the proteins and enzymes. For example GST P1-1 interacts with c-Jun N-terminal kinase 1 (JNK1) suppressing the basal kinase activity. GST P1-1 also has a role in protection and cell survival after exposure to H2O2 but not against UV-induced apoptosis . Whereas, mouse GST M1-1 protects cells against both UV-and H2O2-induced cell death and binds to apoptosis signal-regulating kinase 1 (ASK1), inhibits its kinase activity . Moreover, mouse GST A4-4 has also been proposed to interact with JNK and prevent cells from 4-hydroxynonenal induced apoptosis , .
3.3.4. The detoxification function of GSTs
As enzymes, GSTs are involved in many different detoxification reactions. They are commonly referred to as phase II enzymes. They catalyze the conjugation of GSH to a wide variety of endogenous and exogenous electrophilic toxic compounds. The GSH conjugates are excreted as mercapturic acids by the phase III metabolic pathway . GST P1-1, GST M1-1 and GST A1-1 have been shown to catalyze the inactivation process of α, β unsaturated carbonyls like acrolein, (a cytotoxic compound present in tobacco smoke), propenals, (generated by oxidative damage to DNA) and alkenals, (formed by oxidative damage to lipids) , .
3.4. GST and aflatoxin
Study on GSTs of
3.4.2. Primary metabolism of aflatoxin B1
Once inside the body and for toxicity to occur, AFB1 undergoes enzymatic conversion to electrophilic endo and exo stereoisomers of AFB1-8,9-epoxide by the action of mixed function mono-oxygenase enzyme systems, CYPs are an intensively studied family of enzymes with currently approximately 4,000 known members. They have been found in almost all branches of the “tree of life”, ranging from microorganisms over plants to mammalians. CYP enzymes are classified into families identified by a number (e.g., 1, 2, 3, and 4), subfamilies identified by a letter (e.g., 2A, 2B, 2D, and 2E), and specific members identified by another number (e.g., CYP2E1 and CYP2A6) , .
In human, five CYP gene families, namely; CYP1, CYP2, CYP3, CYP4 and CYP7 are believed to play crucial roles in hepatic as well as extra-hepatic metabolism and elimination of xenobiotics , , . This superfamily of hemoproteins aids in the oxidation of various substrates such as steroids, eicosanoids, pharmaceuticals, pesticides, pollutants, and carcinogens . As mentioned earlier, they bioactivate AFB1 to an electrophilic, highly reactive and unstable metabolite known as aflatoxin-8,9-epoxide, which binds to guanine residues in nucleic acids, leading to irreversible damage in DNA and causing hepatocarcinoma in humans, primates, and ducks , . However, only AFB1 exo-epoxide (AFBO), binds appreciably to DNA (Figure 2). The AFBO is highly unstable, and it reacts with cellular nucleophiles and can induce mutations by alkylating DNA, principally at the N7 position of guanine forming the 8,9-dihydro- 8-(N7-guanyl)-9-hydroxy-AFB1. In addition, AFBO can bind to proteins and other critical cellular nucleophiles , . Initial studies reported that concentrations of AFB1 which are likely to be achieved in the liver following ingestion of ‘‘real-world” concentrations of AFB1 are bioactivated to AFBO primarily by CYP1A2, whereas much higher concentrations are catalyzed by CYP3A4 , , . A recent study demonstrated a dominant contribution of CYP3A4 homologues in AFBO production. AFB1 metabolism studies in human liver microsomal preparations indicate a predominant role for CYP3A4 and that its expression level was an important determinant of the AFB1 disposition in human liver . Specific CYP3A4 inhibitors like troleandomycin have been shown to inhibit AFBO production , while inducers of CYP3A4 activity such as 3-methylcholanthrene and rifampicin, increase AFB1 metabolism in cultured human hepatocytes .
CYP1A homologues also metabolize AFB1 to produce the detoxified metabolite AFM1, whereas CYP3A enzymes - P450 III AY and in the fetal liver P450 III A6
- P450 III AY and in the fetal liver P450 III A6
CYPs may also catalyze demethylation to aflatoxin P (AFP1) of the parent AFB1 molecule, resulting in products less toxic than AFB1. Other major metabolites in the human include aflatoxicol (AFL), AFLH1, AFB2á and AFB1-2, 2-dihydrodiol .
3.4.3. Secondary metabolism of aflatoxin B1
Oxidative metabolism of AFB1 by cytochrome P450 results in the formation of several products such as AFB1-epoxide which serve as substrates for phase II detoxification enzymes. Phase II enzymes such as GSTP1 and GSTA1, found in several mammalian species and non-tumorous liver tissues  are the first step in the mercapturic acid pathway, which leads to the excretion of the xenobiotics. Because conjugation of the electrophilic AFB1-8,9-epoxide with GSH is an alternative fate to binding to nucleophilic centers in cellular macromolecules, GSTs play a critical role in the protection of tissues from the deleterious effects of bioactivated AFB1, and tissues vary considerably in both GST concentration and distribution of specific GST isoforms. Two stereoisomers of AFB1-8,9-epoxide were identified: AFB1 exo-epoxide and AFB1 endo-epoxide, and their corresponding GSH conjugates; AFB1 exo-epoxide-GSH and AFB1 endo-epoxide-GSH. It has been reported that only the exo-epoxide effectively interacts with DNA and was at least 500-fold more potent as a mutagen than the endo stereoisomer. , .
Throughout the animal kingdom, significant variations exist in the susceptibility of different species to AFB1. Man and rats are sensitive to AFB1 but mice can tolerate this mycotoxin. . In man and rat as well as many mammalian species, AFB1-8,9-epoxide is efficiently conjugated with reduced glutathione. Little is known about the identity of the GST which is responsible for detoxifying activated AFB1. To date, the catalytic conjugation of AFB1-8,9-epoxide has only been reported using rat and mouse GST as enzyme source and the ability of GST in other species to catalyze this reaction has not been described. In the investigation on hepatic rat GST responsible for catalyzing the conjugation of AFB1-8,9-epoxide with GSH, it has been shown that the alpha class but not mu-class of GST possess greatest ability to metabolize activated AFB1. Although the rat pi-class GST cannot catalyze this reaction it might be expected that the theta-class enzyme GST is active towards AFB1-8,9-epoxide. By contrast with the rat, the mouse exhibits high constitutive levels of GST activity towards AFB1-8,9-epoxide and alpha-class GST in Swiss-Webster mice possess high activity towards AFB1-8,9-epoxide and can protect against DNA-binding by AFB1 metabolites. Neither the murine mu-class nor pi-class GST can detoxify activated AFB1 and all the activity towards this substrate is contributed by the alpha-class GST. It can be concluded that in the mouse the theta-class enzymes do not play a major role in the detoxification of activated AFB1. Hamster liver contains significant levels of AFB1-GSH-conjugating activity but the GST involved have not been characterized. In human liver, GST does not appear to play as important a role in providing protection against AFB1 as the rodent GST. The
Besides the formation of GSH conjugates, glucuronide and sulfate conjugates of AFB1 have also been described in a variety of species including rat, mouse, monkey and trout. The ability to form these alternative secondary metabolites may be of considerable physiological importance in species, like the trout, that are unable to produce AFB1-GSH conjugates. Before AFB1 can form glucuronide and sulfate conjugates it requires to be hydroxylated. The primary metabolites AFM1, AFP1, and AFQ1 can readily form glucuronide or sulfate conjugates. Whilst such conjugation reactions may aid excretion of aflatoxin, their toxicological value is unclear as such hydroxylated metabolites are not particularly harmful because they are not subject to 8,9-epoxidation. However, it has been proposed that AFB1 is itself capable of forming glucuronide and sulfate conjugate; these reactions might entail a molecular rearrangement possibly involving the addition of water to the keto group in the cyclopentone ring, that result in the introduction of a hydroxyl group into the AFB1 structure. This proposal is of particular interest as it enables the direct detoxification of AFB1 through reactions that may not involve cytochrome P450. These workers have also proposed that amines, thiols and alcohols might also be conjugated to AFB1 via the keto group in the cyclopentone ring .
Alternatively, the AFB1-epoxide can hydrolyse spontaneously to AFB1-dihydrodiol. This is not a true detoxification process as the dihydrodiol product can rearrange at neutral pH values to form a dialdehydic phenolate ion. This AFB1-dialdehyde can undergo Schiff-base formation with primary amine groups in proteins and is therefore likely to be cytotoxic. Recently, a novel AFB1-aldehyde reductase (AFB1-AR) purified from ethoxyquin (EQ)-treated rat liver has been shown to metabolize the dialdehyde form of AFB1-dihydrodiol to an AFB1-dialcohol and its relative importance in AFB1 detoxification may be considerable . The toxicity of AFB1 is selective towards certain species. In contrast with the mouse and hamster, the rat, guinea pig and man are susceptible to the hepatotoxic effects of AFB1 . The toxicity of the mycotoxin is based on a balance between the rate of primary activation of AFB1 and the rate of detoxification of primary metabolites or repair of cellular damage, determined by the relative activity of enzymes responsible for these reactions; the differential toxicity of AFB1, between species is thought to be due mainly to different levels of activity of xenobiotic-metabolizing enzymes. In this regard, the livers of mice which are resistant to the hepatoxic effects of AFB1 contain high concentrations of a Yc-type GST subunit  that has considerable GSH conjugating activity towards AFB1-epoxide , , , . By contrast, the Fischer rat, an inbred strain that is five times more susceptible to AFB1- induced liver cancer than the Wistar rat , possesses 20-fold less hepatic AFB1-GSH-conjugating activity than the mouse. Fischer rats can, however, be protected against AFB1 by treatment with the antioxidant EQ. It has shown that following EQ-treatment the livers of Fischer rats express a GST subunit that is immunochemically related to the mouse Yc subunit . Moreover, this inducible polypeptide (Yc2, subunit 10) has high activity towards AFB1-epoxide . Thus, the Yc2 subunit is thought to confer protection against AFB1, and its induction by EQ is likely to be one of the key mechanisms for the protective action of this anti-carcinogen .
The transport of foreign compounds out of cells can be achieved by at least two distinct families of efflux pump, both of which may provide protection against AFB1 by helping eliminate the mycotoxin from target cells. The best characterized of these two pumps is P-glycoprotein, the product of the
Relatively little is known about the enzymes responsible for the removal of AFB1 that is bound covalently to DNA in mammalian cells. Exposure of cells to AFB1 results in the formation of three major adducts. Of these, trans-2,3-dihydro-2-(N7-guanyl)-3-hydroxy AFB1 (AFB1- N7 G) is the most abundant. It is chemically unstable and is lost spontaneously from DNA
3.4.4. Conclusion and future directions
Evidences presented in this review article clearly show that glutathione conjugation to aflatoxin metabolites which has been detected in aflatoxin-producing fungi as well as liver tissues of mammalians play a crucial role in reducing the interaction of aflatoxins with cellular macromolecules. However further studies is needed to answer the main questions about the contribution of glutathione conjugation system in removing aflatoxin in different cellular systems. The future direction of this topic is to find out experimental-based answers to the following questions:
What is the relationship between the rate of aflatoxin metabolism and the level of aflatoxin-GSH conjugate formation?
Which classes of glutathione S-transferases in each cellular system is directly responsible for involvement of aflatoxin-GSH conjugate formation
What is the relationship between the efficiency of glutathione conjugation system and toxic action of aflatoxins in different cell systems.
It is the time to express the deepest gratitude to Mr. Hamed Foroozesh for whole-hearted support and for his devoted care. Thanks for his vast knowledge and skill in many areas and his assistance.
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- - Plants like potatoes, tomatoes, peppers, egg plant, tobacco, some spices.
- - Like bitter almond, cassava root, sorghum root, lima bean, fruit seed, etc.
- - Chemical compounds foreign to the human organism without nutritional value
- - A group of mycotoxins of which aflatoxin B1 is the most potent hepatocarcinogen
- - A toxin producing by cyanobacteria of which microcystin-LR is predominant
- - Glutathione, reduced form
- - Glutathione, oxidized state
- - 1-chloro-2,4-dinitrobenzene
- - P450 III AY and in the fetal liver P450 III A6