Biotransformation and renal processing of nephrotoxic agents

Nephrotoxicity is often observed as an endpoint in animal toxicity studies. In recent years, the mechanisms of biotransformation, which often provide the basis for renal toxicity, have been elucidated for a variety of compounds. These studies showed that nephrotoxicity of chemicals is either due to accumulation of certain metabolites in the kidney and further bioactivation or due to intrarenal bioactivation of the parent xenobiotic. Both types of mechanisms will be discussed using two relevant samples. The polychlorinated olefin hexachlorobutadiene and other haloolefins cause necrosis of the S-3 segment of the proximal tubules; their nephrotoxicity is dependent on bioactivation reactions. In the liver, hexachlorobutadiene is transformed by conjugation with glutathione to (S-pentachlorobutadienyl)glutathione. This S-conjugate is processed by the enzymes of mercapturic acid formation to give N-acetyl-(S-pentachlorobutadienyl)-L-cysteine, which is accumulated in the proximal tubule cells and deacetylated there to give (S-pentachlorobutadienyl)-L-cysteine. Further bioactivation is catalyzed by renal cysteine conjugate beta-lyase. Both the renal accumulation by the organic anion transporter and the topographical distribution of cysteine conjugate beta-lyase along the nephron are major determinants of organ and cell selectivity. Vinylidene chloride (VDC) is nephrotoxic in mice after inhalation, but not after oral or intraperitoneal administration. The nephrotoxicity of VDC is due to the selective expression of an androgen-dependent cytochrome P450 in the proximal tubules of male mice. This enzyme oxidizes VDC to an electrophile and is not present in female mice, but can be induced be androgen treatment. The observation of nephrotoxicity of VDC after inhalation only is due to the high blood flow to the kidney and thus high concentrations of VDC delivered to the kidney after inhalation. After oral or intraperitoneal application, hepatic first-pass metabolism efficiently reduces the amount of VDC delivered to the kidney. The results demonstrated here demonstrate that prior to in vitro nephrotoxicity screening, toxicokinetics and biotransformation pathways for a chemical have to be elucidated and metabolites have to be included into the testing regimen.