Glutathione S-transferase in chemotherapy resistance and in carcinogenesis.
Cytosolic glutathione S-transferases are composed of two monomeric subunits. These monomers are the products of different gene families designated alpha, mu, and pi. Dimerization yields either homodimeric or heterodimeric holoenzymes within the same family. The members of this complex group of proteins have been linked to the detoxification of environmental chemicals and carcinogens, and have been shown to be overexpressed in normal and tumor cells following exposure to cytotoxic drugs. They also are overexpressed in carcinogen-induced rat liver preneoplastic nodules in rat liver. In all of these cases, the changes in expression of glutathione S-transferases are paralleled by increased resistance to cytotoxic chemicals. The degree of resistance is related to the substrate specificity of the isozyme. The relationship of the glutathione S-transferase genes to drug resistance has been directly demonstrated by gene transfer studies, where cDNAs encoding the various subunits of glutathione S-transferase have been transfected into a variety of cell types. This review discusses the results of numerous studies that associate resistance to alkylating agents with overexpression of protective detoxifying glutathione S-transferase enzymes.
Department of Medicine, Montréal General Hospital Research Institute-McGill University, Que., Canada.
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Schecter
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Alaoui-Jamali
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Batist
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000477:Alkylating Agents / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism; D004351:Drug Resistance; D004790:Enzyme Induction; D005796:Genes; D005982:Glutathione Transferase / Q000235:genetics / Q000502:physiology*; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000201:enzymology; D051381:Rats
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000477:Alkylating Agents; D000970:Antineoplastic Agents; D002273:Carcinogens; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D005982:Glutathione Transferase