Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology

Bolt, H. M. & Thier, R. (2006) Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology. Current Drug Metabolism, 7(6), pp. 613-628.

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Although cytosolic glutathione S-transferase (GST) enzymes occupy a key position in biological detoxification processes, two of the most relevant human isoenzymes, GSTT1-1 and GSTM1-1, are genetically deleted (non-functional alleles GSTT10 and GSTM10) in a high percentage of the human population, with major ethnic differences. The structures of the GSTT and GSTM gene areas explain the underlying genetic processes. GSTT1-1 is highly conserved during evolution and plays a major role in phase-II biotransformation of a number of drugs and industrial chemicals, e.g. cytostatic drugs, hydrocarbons and halogenated hydrocarbons. GSTM1-1 is particularly relevant in the deactivation of carcinogenic intermediates of polycyclic aromatic hydrocarbons. Several lines of evidence suggest that hGSTT1-1 and/or hGSTM1-1 play a role in the deactivation of reactive oxygen species that are likely to be involved in cellular processes of inflammation, ageing and degenerative diseases. There is cumulating evidence that combinations of the GSTM10 state with other genetic traits affecting the metabolism of carcinogens (CYP1A1, GSTP1) may predispose the aero-digestive tract and lung, especially in smokers, to a higher risk of cancer. The GSTM10 status appears also associated with a modest increase in the risk of bladder cancer, consistent with a GSTM1 interaction with carcinogenic tobacco smoke constituents. Both human GST deletions, although largely counterbalanced by overlapping substrate affinities within the GST superfamily, have consequences when the organism comes into contact with distinct man-made chemicals. This appears relevant in industrial toxicology and in drug metabolism.

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ID Code: 77442
Item Type: Journal Article
Refereed: Yes
Keywords: Cancer, Chronic diseases, Deletion polymorphisms, Enzyme polymorphisms, Glutathione S-transferases, GSTM1, GSTT1, 1, 2 epoxy 3 butene, 3, 4 epoxy 1, 2 dihydroxychrysene, antimalarial agent, benz[a]anthracene derivative, benzene, benzylideneacetone, biochemical marker, carcinogen, carmustine, chrysene derivative, cytochrome P450 1A1, cytostatic agent, dibenz[a, h]anthracene diol epoxide, dichloromethane, dihydroxybenzo[a]pyrene oxide, ethylene oxide, glutathione transferase M1, glutathione transferase T1, halogenated hydrocarbon, hydrocarbon, lipid hydroperoxide, polycyclic aromatic hydrocarbon, quinidine, quinine, reactive oxygen metabolite, stilbene oxide, styrene oxide, tobacco smoke, tuberculostatic agent, unclassified drug, unindexed drug, aging, allele, asthma, atherosclerosis, bladder cancer, brain cancer, breast cancer, cancer risk, carcinogenicity, cardiovascular disease, chronic disease, chronic inflammation, chronic obstructive lung disease, cigarette smoking, cytosol, degenerative disease, detoxification, digestive system cancer, drug metabolism, drug transformation, enzyme substrate, ethnic difference, gene deletion, gene structure, genetic conservation, genetic polymorphism, genetic predisposition, genetic trait, genetic variability, head and neck cancer, high risk patient, human, leukemia, liver cancer, liver toxicity, lung cancer, metabolic regulation, molecular evolution, molecular phylogeny, nonhuman, pharmacogenetics, population genetics, prostate cancer, protein family, respiratory tract cancer, review, rheumatoid arthritis, systemic lupus erythematosus, Alleles, Animals, Cardiovascular Diseases, Glutathione Transferase, Humans, Lipid Peroxidation, Neoplasms, Phylogeny, Polycyclic Hydrocarbons, Aromatic, Polymorphism, Genetic, Pulmonary Disease, Chronic Obstructive, Reactive Oxygen Species
DOI: 10.2174/138920006778017786
ISSN: 1389-2002
Divisions: Current > Schools > School of Clinical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Copyright Owner: Copyright 2006 Bentham Science Publishers Ltd.
Deposited On: 21 Oct 2014 00:10
Last Modified: 22 Oct 2014 00:58

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