The kidney as a target for biological reactive metabolites: linking metabolism to toxicity.

Abstract

The conjugation of potentially toxic electrophiles with glutathione (GSH), the process of thioether formation, is usually associated with detoxication and excretion (Sies and Ketterer, 1988). Compounds that are conjugated with GSH are usually excreted in urine as their corresponding mercapturic acids, S-conjugates of N-acetylcysteine. The kidney is susceptible to chemical induced injury, and GSH conjugation seems to play a major role in the bioactivation of many of renal toxicants. Halogenated alkanes and alkenes are targeted to the kidney via GSH conjugation, and subsequent bioactivation of the corresponding cysteine conjugate by cysteine conjugate β-lyase (Dekant et al., 1994). Polyphenols also seem to be targeted to the kidney via extra-renal conjugation with GSH (Monks and Lau 1994a) and tissue selectivity in this instance appears to be conferred by the high activity of γ-glutamyl transpeptidase on the brush border membrane of renal proximal tubular epithelial cells. Thus, in contrast to the generally accepted role of GSH conjugation serving as a detoxication mechanism conjugation of quinones with GSH results in the formation of potent, and selective, nephrotoxicants (Monks et al., 1985, 1988; Lau et al., 1988, 1990; Mertens et al., 1991), and evidence has accumulated suggesting that GSH conjugation of quinones may be a common mechanism of bioactivation (Monks and Lau, 1992).KeywordsBrush Border MembraneGlutathione ConjugateMercapturic AcidButhionine SulfoximineCysteine ConjugateThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.