The Role of Human Glutathione Transferases and Epoxide Hydrolases in the Metabolism of Xenobiotics
Janeric Seidegård1 and Gunilla Ekström2
1Human Pharmacology at Astra Draco AB, Lund, Sweden,
2Drug Metabolism at Astra Pain Control AB, Södertälje, Sweden
Abstract
Human glutathione transferases (GSTs) are a multigene family of enzymes that are involved in the metabolism of a wide range of electrophilic compounds of both exogenous and endogenous origin. GSTs are generally recognized as detoxifying enzymes by catalyzing the conjugation of these compounds with glutathione, but they may also be involved in activation of some carcinogens. The mammalian GSTs can be differentiated into four classes of cytosolic enzymes and two membrane bound enzymes. Human epoxide hydrolases (EHs) catalyze the addition of water to epoxides to form the corresponding dihydrodiol. The enzymatic hydration is essentially irreversible and produces mainly metabolites of lower reactivity that can be conjugated and excreted. The reaction of EHs is therefore generally regarded as detoxifying. The mammalian EHs can be distinguished by their physical and enzymatic properties. Microsomal EH (mEH) exhibits a broad substrate specificity, while the soluble EH (sEH) is an enzyme with a "complementary" substrate specificity to mEH. Cholesterol EH and leukotriene A4 hydrolase are two EHs with very limited substrate specificity.The activities of either GSTs or EHs expressed in vivo exhibit a relatively large interindividual variation, which might be explained by induction, inhibition, or genetic factors. These variations in levels or activities of individual isoenzymes are of importance with respect to an individual's susceptibility to genotoxic effects. This article gives a general overview of GSTs and EHs, discussing the modulation of activities, determination of these enzymes ex vivo, and the polymorphic expression of some isoenzymes. -- Environ Health Perspect 105(Suppl 4):791-799 (1997)
Key words: human, glutathione transferase, epoxide hydrolase, xenobiotics, polymorphism
This paper was prepared as background for the Workshop on Susceptibility to Environmental Hazards convened by the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC) held 17-22 March 1996 in Espoo, Finland. Manuscript received at EHP 5 November 1996; accepted 18 November 1996.
Address correspondence to Dr. J. Seidegård, Human Pharmacology, Astra Draco AB, P.O. Box 34, S-221 00 Lund, Sweden. Telephone: +46 46 336660, Fax: +46 46 337191. E-mail: janeric.seidegard@draco.se.astra.com
Abbreviations used: BHA, butylated hydroxyanisole; BHT, butylated hydroxytoluene; BP, benzo[a]pyrene; BPO, benzo[a]pyrene oxide; CCl4, carbon tetrachloride; CDNB, 1-chloro-2,4-dinitrobenzene; EH, epoxide hydrolase; GSH, glutathione; GSSG, glutathione disulfide; GST, glutathione transferase; LTA4, leukotriene A4; LTB4, leukotriene B4; LTC4, leukotriene C4; NEM, N-ethylmaleimide; PAH, polycyclic aromatic hydrocarbon; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; SCE, sister chromatid exchange.
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Last Update: June 16, 1997