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Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Although GSH conjugation is in general a detoxification pathway for xenobiotic biotransformation, an increasing number of xenobiotics are known to be bioactivated by this pathway [reviewed by Anders et al. (1988) and Lock (1988)]. γ-Glutamyltransferase (EC 2.3.2.2.) and dipeptidases (EC 3.4.13.6., 3.4.11.2.), respectively, catalyze the removal of the glutamyl and glycine moieties of the glutathione S-conjugates to yield the corresponding cysteine S-conjugates. Cysteine S-conjugates are the penultimate toxic metabolites of nephrotoxic halogenated alkenes. These conjugates may form electrophiles nonenzymatically, be detoxified by acetylation to a mercapturic acid by cysteine S-conjugate N-acetyltransferase (EC 2.3.1.80.), or be biotransformed by cysteine conjugate β-lyase (EC 2.6.1.64.) to toxic and/or nontoxic thiols. Some of the thiols formed by cysteine S-conjugate β-lyase can be further biotransformed to toxic and/or nontoxic methylthio derivatives by S-methyltransferases (see below). The selectivity for kidney toxicity is due to the active transport of the S-cysteine conjugates by the renal anion transport system, urinary excretion of the conjugates, and kidney localization of cysteine S-conjugate β-lyase. For hepatotoxicity, GSH conjugation plays a role in the bioactivation of vicinal dihaloethanes, such as 1,2-dibromoethane. The gluthione-S-conjugate mustards of these compounds nonenzymatically form electrophilic episulfonium ions.
The mercapturic acid pathway
Published in Critical Reviews in Toxicology, 2019
Patrick E. Hanna, M. W. Anders
Cysteine S-conjugate N-acetyltransferase (NAT8) has been implicated in the regulation of blood pressure and kidney function, and several studies support a role for aminoacylase-1 (Acy1) as a regulator of tumor growth.