Bioactivation of nephrotoxins and renal carcinogens by glutathione S-conjugate formation.

Evidence has been accumulating that several classes of compounds are converted by glutathione conjugate formation to toxic metabolites. The aim of this review is to summarize the current knowledge on the biosynthesis and toxicity of glutathione S-conjugates derived from halogenated alkenes, and hydroquinones and quinones. Different types of toxic glutathione conjugates have been identified in detail; (i) conjugates which are converted to toxic metabolites in an enzyme-catalyzed multistep mechanism and (ii) conjugates which serve as a transport form for toxic quinones will be discussed. The kidney is the main, with some compounds the exclusive, target organ for compounds metabolized by these pathways. Selective toxicity to the kidney is easily explained due to the capability of the kidney to accumulate intermediates formed by processing of S-conjugates and to bioactivate these intermediates to toxic metabolites. The influences of other factors participating in the renal susceptibility and influencing human risk assessment for these compounds are discussed.