Role of renal metabolism in risk to toxic chemicals.

The kidneys are capable of carrying out extensive oxidation, reduction, hydrolysis, and conjugation reactions. Renal cortex has high activities of cytochrome P450 and glutathione (GSH) S-transferase. In contrast, renal medulla has high activity of prostaglandin synthetase, which can catalyze co-oxidation of xenobiotics. While these pathways are found in many tissues and at higher activities than in kidney, several key enzymes of the mercapturic acid pathway are found at especially high activities in cells of the renal proximal tubule. Investigations over the last two decades demonstrated that GSH conjugation is not only a mechanism for detoxification of reactive electrophiles. Rather, metabolism of GSH S-conjugates to the corresponding cysteine S-conjugates represents a branch point: cysteine S-conjugates may be metabolized by the cysteine S-conjugate N-acetyl-transferase to mercapturic acids, which are nontoxic and are excreted, or they may be substrates for the pyridoxal phosphate-dependent cysteine conjugate beta-lyase, which catalyzes either a beta-elimination or a transamination reaction to produce unstable thiols. These thiols rearrange to form potent acylating species that can covalently bind to cellular macromolecules, thereby producing cytotoxicity, mutagenicity, and carcinogenicity. In addition to the beta-lyase, two other renal enzymes, L-2-amino (2-hydroxy) acid oxidase and cysteine conjugate S-oxidase, can bioactivate chemicals to produce nephrotoxic species. Several halogenated alkanes and alkenes are bioactivated by these pathways. These findings show that mammalian kidney is highly active in bioactivation of xenobiotics. Although the properties of the corresponding enzymes in humans may differ, it is clear that renal metabolism can be a critical determinant of risk to chemical injury.