Glutathione-dependent toxicity.
1. Recent studies show that glutathione conjugate formation is an important bioactivation mechanism for several groups of compounds with implications for organ-selective toxicity and carcinogenicity. 2. Vicinal dihaloalkanes, such as 1,2-dihaloethanes, yield S-(2-haloalkyl)glutathione conjugates that give rise to highly electrophilic episulphonium ions, which are involved in the cytotoxicity and mutagenicity of 1,2-dihaloethanes. 3. Nephrotoxic haloalkenes are metabolized to S-(haloalkenyl)- or S-(haloalkyl)-glutathione conjugates which, after metabolism to the corresponding cysteine conjugates, are bioactivated by renal cysteine conjugate beta-lyase to yield cytotoxic or mutagenic metabolites. 4. Finally, hepatic glutathione conjugate formation with hydroquinones and aminophenols yields conjugates that are directed to gamma-glutamyltransferase-rich tissues, such as the kidney, where they undergo alkylation or redox cycling reactions, or both, that cause organ-selective damage.
Anders
M W
MW
Department of Pharmacology, University of Rochester, New York 14642.
Dekant
W
W
Vamvakas
S
S
D000627:Aminophenols / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D005978:Glutathione / Q000378:metabolism*; D006846:Hydrocarbons, Halogenated / Q000493:pharmacokinetics / Q000633:toxicity; D006873:Hydroquinones / Q000493:pharmacokinetics / Q000633:toxicity; D015262:Xenobiotics / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*
D000627:Aminophenols; D006846:Hydrocarbons, Halogenated; D006873:Hydroquinones; D015262:Xenobiotics; D005978:Glutathione