Glutathione S-epoxide transferase

This epoxidation of AFB has been associated with aldrin epoxidase (AE) activity in trout (30). As with other epoxide carcinogens, OAFB may be a substrate 7or epoxide metabolizing enzyme systems such as epoxide hydrase (EH) (EC4.2.1.63) and glutathione-S-epoxide transferase (GTr) (EC4.4.1.7) found in mammals and fish (31, 32, 33, 34). AFB also undergoes a variety of other reactions, generally to less toxic metabolites depending on the species of animal involved (35, 36). The primary AFB metabolite in rainbow trout has been shown to be a reduced form of AFB, aflatoxicol (AFL) (24). 

Comparison of the reactivities of benzene oxides, naphthalene oxides, phenanthrene oxides, and arene oxides derived from benzo [a] pyrene and 7,12-dimethylbenz[a] anthracene with hepatic glutathione S-epoxide transferase showed that benzene oxides without electron-withdrawing groups are poor substrates as also are polycyclic arene oxides. Only naphthalene oxide was a good substrate. 

The latter reaction sequence was of importance since addition of the thiol glutathione to arene-oxide intermediates under control of hepatic glutathione-S-epoxide transferase enzyme(s) is a very important metabolic transformation. It would appear probable that most of the structures of the arene oxide-glutathione adducts (premercapturic acids) reported in the literature before 1975 are incorrect with respect to the position of the hydroxy and thioether substituents (they should now be reversed). Addition of thiomethoxide anion to arene oxide 70 may occur via 1,6- and 1,4-addition, although one of these thioether adducts could also be accounted for by the alternative arene-oxide intermediate obtained from an oxygen-walk. Styrene 3,4-oxide (S3) has been observed to react with ethanethiol to yield three adducts which appear to aromatize to three isomeric ethylthiostyrenes without the formation of episulphonium intermediates. ... 

Epoxides of aromatic rings (arene oxides) rearrange to phenols and are substrates for glutathione-S-epoxide transferase to give glutathione conjugates, the precursors of mercapturic acids (Boyland and Williams 1965). 

In addition to direct oxygenation, e.g. by aryl hydrocarbon hydroxylase, oxidative N- or 0-dealkylation is another process catalyzed by components of the Cytochrome P-450 System (mixed-function oxidases). Reduction also occurs in this system NADPH-cytochrome P-450 reductase has an activity similar to microsomal nitroreductase, i.e. transformation of aronaatic nitro compounds into the corresponding arylamines takes place. The oxidation may be followed by other enzymic reactions, e.g. epoxides are hydrated to vicinal diols by microsomal epoxide hydratase or they are coupled with glutathione by glutathione-S-epoxide transferase. 

Figure 23-7. Conversion of arachidonicacid to leukotrienesand lipoxins of series 4 via the lipoxygenase pathway. Some similar conversions occur in series 3 and 5 leukotrienes. (HPETE, hydroperoxyeicosatetraenoate HETE, hydroxyeicosatetraenoate , peroxidase (2), leukotriene A4 epoxide hydrolase , glutathione S-transferase ...

J. G. Hengstler, M. Arand, M. E. Herrero, F. Oesch, Polymorphism of A-Acetyltransfe-rase, Glutathione S-Transferases, Microsomal Epoxide Hydrolase and Sulfotransferase Influence on Cancer Susceptibility , Recent Results Cancer Res. 1998, 154, 47 - 85. 

Thiol conjugation Epoxides Glutathione S-transferases (glutathione or N-acetylcysteine) Glutathione or N-acetyl cysteine thioethers... 

The oxidation of naphthalene was one of the earliest examples of an epoxide as an intermediate in aromatic hydroxylation. The epoxide can rearrange nonenzymatically to yield predominantly 1-naph-thol, interact with the enzyme epoxide hydrolase to yield the dihydrodiol, or interact with glutathione S-transferase to yield the glutathione conjugate, which is ultimately metabolized to a mer-capturic add. 

Fish are extremely good biliary concentrators of drugs. Molecular weight and polarity concerns for biliary elimination are basically similar to mammals, but bile formation in fish is nearly 50 times slower than mammals. As a result, fish have the capacity to biotransform a variety of substrates, although the rates generally observed are lower than in many mammalian species. Sufficient evidence exists to indicate that glucuronyl transferase, sulfotransferase, glutathione-S-transferase, and epoxide hydrolase activities in fish are, at least qualitatively, similar to those found in mammals (23, 24). 

A, B, U metabolites in exhaled air, blood, urine, respectively CYP, cytochrome P450 GST, glutathione-S-transferase EH, epoxide hydrolase dashed frame metabolites forming DNA or haemoglobin adducts [ ] proposed metabolites not yet detected dashed lines, assumed pathways number assignment according to Nauhaus et al. (1996)... 

J.K. Wiencke, K.T. Kelsey, R.A. Lamela, W.A. Toscano, Jr, Human Glutathione-S-transferase Deficiency as a Marker of Susceptibility to Epoxide-induced Damage , Cancer Res., 50,1585-1590 (1990). 

N. P. Genetic Polymorphisms of Human V-acetyltrans-ferase, Cytochrome P450, Glutathione-S-transferase, and Epoxide Hydrolase Enzymes Relevance to Xenobiotic Metabolism and Toxicity. Crit. Rev. Toxicol. 1999, 29, 59-124. 

Chengelis, C.P., Age- and sex-related changes in epoxide hydrolase, UDP-glucuronosyl transferase, glutathione S-transferase, and PAPS sulphotransferase in Sprague-Dawley rats, Xenobiotica, 18,1225,1988. 

Mukhtar, H., R.M. Philpot, and J.R. Bend. The postnatal development of microsomal epoxide hydrase, cytosolic glutathione S-transferase, and mitochondrial and microsomal cytochrome P-450 in adrenals and ovaries of female rats. Drug Metab. Dispos. 6 577-583, 1978. 

Gupta RC, Atul BV (2000) Drug metabolism studies in animal models. Ind 1 Pharmacol 32 S62-S66 Hassett C, Lin 1, Carty CL et al. (1997) Human hepatic microsomal epoxide hydrolase comparative analysis of polymorphic expression. Arch Biochem Biophys 337 275-283 Hengstler 1G, Arand M, Herrero ME, Oesch F (1998) Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfo-transferases influence on cancer susceptibility. Recent Results Cancer Res 154 47-85... 

Wormhoudt LW, Commandeur JN, Vermeulen NP (1999) Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 29 59-124... 

Since liver is the most important organ for metabolism investigations the procedures described here focus on liver cytosol exemplarily. Liver cytosol fraction contains soluble Phase I and Phase II enzymes which play an important role in drug metabolism (Brandon 2003). These are alcohol and aldehyde dehydrogenases, epoxide hydrolases, sulfotransferases, glutathione S transferase, N-acetyl transferases, and methyl transferases. Therefore, in cytosolic preparations these biotransformation steps can be studied. Cytosolic fractions are commercially available (BDGentest, Invitro Technologies, Xenotech and others) or easy to prepare, alternatively. 

Raney KD, Meyer DJ, Ketterer B et al. (1992) Glutathione conjugation of aflatoxin B1 exo-and endo-epoxides by rat and human glutathione S-transferases. Chem Res Toxicol 5 470-478... 

Slone DH, Gallagher EP, Ramsdell HS et al. (1995) Human variability in hepatic glutathione S-transferase-mediated conjugation of aflatoxin B 1-epoxide and other substrates. Pharmacogenetics 5 224-233... 

The importance of the cytochrome P450 monooxygenases, glutathione S-transferases, car-boxylesterases, and epoxide hydrolases in insecticide metabolism and detoxification, as well as in insecticide resistance, is well documented. It is, therefore, logical to expect that an increase in these enzyme activities resulting from induction by xenobiotics would decrease the toxicity of an insecticide because of enhanced metabolism (see review by Yu, 1986a). 

Hengstler JG, Arand M, Herrero ME, Oesch F. Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfo-transferases Influence on cancer susceptibility. Recent Results Cancer Res 1998 154 47-85. 

---