RENAL ACTIVATION OF TRICHLOROETHENE AND S-(1,2-DICHLOROVINYL)-L-CYSTEINE AND CELL PROLIFERATIVE RESPONSES IN THE KIDNEYS OF F344 RATS AND B6C3F1 MICE

Covalent binding of reactive intermediates formed by renal beta-lyase activation of S-(1,2-dichlorovinyl)-L-cysteine (DCVC) has been suggested to be responsible for the greater renal sensitivity of rats than mice to the carcinogenic effects of chronic treatment with trichloroethene (TRI). Previous work demonstrated that the activation of DCVC results in acid-labile adducts to protein that can be distinguished from adducts formed by other pathways of TRI metabolism. By analyzing acid-labile adduct formation, the relationship between DCVC formation and activation from TRI and increases in rates of cell division in the kidneys of male F344 rats and B6C3F1 mice could be investigated. The delivered dose of DCVC from an oral dose of 1000 mg/kg TRI was approximately six times greater in rats than mice. However, renal activation of DCVC in mice was approximately 12 times greater than in rats. Therefore, the overall activation of TRI was about two times greater in mice than rats. induction of cell replication in liver and kidney following doses of 1, 5, or 25 mg/kg DCVC or 1000 mg/kg TRI was also measured through the use of miniosmotic pumps that delivered BrdU subcutaneously for 3 d. Acid-labile adduct formation from DCVC and TRI displayed a consistent relationship with increased cell replication in mice and between mice and rats. Both cell replication and acid-labile adduct formation in rats given 25 mg/kg DCVC were approximately equal to that observed in mice given 1 mg/kg. Increased cell replication was not observed in rats receiving 1 or 5 mg/kg DCVC or 1000 mg/kg TRI, nor were there histological signs of nephrotoxicity. Thus, net activation of TRI by the cysteine S-conjugate pathway was found to be greater in mice than rats and these findings appeared related to differences in cell proliferative responses of the kidneys of the two species. Based on these data, it would appear that other factors must contribute to the greater sensitivity of the rat to the induction of renal carcinogenesis by TRI.