Is the Toxicity of Cysteine Conjugates Formed During Mercapturic Acid Biosynthesis Relevant to the Toxicity of Covalently Bound Drug Residues?

Abstract

In this brief review, we have focused on the relevance of the data on cysteine conjugate toxicity to the potential hazard of bound drug residues. A resonable scenario, based on assumptions as well as literature data, has been presented for the release of cysteine conjugates of drug residues from protein. Furthermore, we have presented evidence that should this occur, the conjugate would be bioavailable. Finally, the mechanisms which could lead to cysteine conjugate-induced toxicity have been discussed. The question which must be answered is, how realistic is the treat of toxicity to the consumer from cysteine-bound drug residues in food products? Based on the data presented here, the danger is minimal, though it cannot be excluded. This is particularly true of the potential for renal complications. However, an important caveat which must not be overlooked is the marked species differences in cysteine conjugate toxicity. Though S-(1,2LD50-dichlorovinyl)-L-cysteine (DCVC) is a renal toxin in rodent models (LD50 = 66-83 mg/kg) [88], a single dose of 4-5 mg/kg causes fatal aplastic anemia in calves [44,59]. Though such a response has never been reported for any other cysteine conjugate, these data must be reckoned with if attempts are made to place acceptable limits on the amount of residues allowable in food products.