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 suggest ed to be responsible for the greater renal sensitivity of rats than mi ce to the carcinogenic effects of chronic treatment with trichloroethe ne (TRI). Previous work demonstrated that the activation of DCVC resul ts in acid-labile adducts to protein that can be distinguished from ad ducts formed by other pathways of TRI metabolism. By analyzing acid-la bile adduct formation, the relationship between DCVC formation and act ivation from TRI and increases in rates of cell division in the kidney s of male F344 rats and B6C3F1 mice could be investigated. The deliver ed 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, t he overall activation of TRI was about two times greater in mice than rats. induction of cell replication in liver and kidney following dose s of 1, 5, or 25 mg/kg DCVC or 1000 mg/kg TRI was also measured throug h the use of miniosmotic pumps that delivered BrdU subcutaneously for 3 d. Acid-labile adduct formation from DCVC and TRI displayed a consis tent 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 his tological signs of nephrotoxicity. Thus, net activation of TRI by tile cysteine S-conjugate pathway was found to be greater in mice than rat s and these findings appeared related to differences in cell prolifera tive responses of the kidneys of the two species. Based on these data, it would appear that other factors must contribute to the greater sen sitivity of the rat to the induction of renal carcinogenesis by TRI.