Glutathione-dependent bioactivation of xenobiotics: implications for mutagenicity and carcinogenicity.
Glutathione conjugate formation is now recognized as an important bioactivation mechanism for several classes of mutagenic and carcinogenic compounds. For example, dihalomethanes, 1,2-dihaloethanes, and 1,2,3-trihalopropanes are metabolized to glutathione conjugates that are direct-acting, i.e., that require no further enzymatic processing, and that are cytotoxic or mutagenic, or both. Nephrotoxic and nephrocarcinogenic haloalkenes are metabolized by a multistep pathway that involves hepatic glutathione S-conjugate formation, conversion of the glutathione S-conjugates to cysteine S-conjugates, translocation of the cysteine S-conjugates to the kidney, and bioactivation by renal cysteine conjugate beta-lyase. Fluoroalkene-derived conjugates are cytotoxic, whereas chloroalkene-derived conjugates are both cytotoxic and mutagenic. Beta-Lyase-dependent bioactivation may account for the observed nephrocarcinogenicity of hexachlorobutadiene, tetrachloroethylene, and trichloroethylene. Finally, glutathione conjugate formation has been implicated in the mutagenicity of Trp-P-2 and N-OH-Trp-P-2 and in the DNA damage produced by 1-methyl-4-phenyl-5-nitroimidazole. Glutathione may also play a role in the toxicity or action of several cancer chemotherapeutic agents, including N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), N-methylformamide, cyclophosphamide, neocarzinostatin, and bleomycin.
Anders
M W
MW
Department of Pharmacology, University of Rochester, New York 14642.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D003545:Cysteine / Q000494:pharmacology; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D005978:Glutathione / Q000502:physiology*; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects*; D009369:Neoplasms / Q000139:chemically induced*; D009593:Nitroimidazoles / Q000494:pharmacology; D051381:Rats; D015262:Xenobiotics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D015262:Xenobiotics; D004247:DNA; D005978:Glutathione; D003545:Cysteine