GLUTATHIONE CONJUGATION OF TRICHLOROETHYLENE IN RATS AND MICE - SEX-DEPENDENT, SPECIES-DEPENDENT, AND TISSUE-DEPENDENT DIFFERENCES

Glutathione (GSH) conjugation of trichloroethylene (Tri) to form S-(1, 2-dichlorovinyl)glutathione (DCVG) has been implicated in the nephroto xicity and nephrocarcinogenicity of Tri, Marked sex-and species-depend ent differences exist, however, in the susceptibility to Tri-induced r enal toxicity, with the male rat being the most susceptible, The prese nt study, therefore, focuses on potential differences in the initial s tep of the GSH pathway, Rates of DCVG formation were measured in suspe nsions of isolated renal cortical cells and isolated hepatocytes from male and female Fischer 344 rats and in kidney and liver microsomes an d cytosol from male and female Fischer 344 rats and B6C3F1 mice to det ermine a sex-and species-dependent differences in GSH conjugation corr elate with susceptibility to renal toxicity from Tri, Rates of gamma-g lutamyltransferase (GGT) with gamma-glutamyl-p-nitroanilide and glycyl glycine as substrates and GSH S-transferase (GST) with 1-chloro-2,4-di nitrobenzene as substrate were also measured in liver and kidney subce llular fractions to provide further information on the biochemical bas is of susceptibility to Tri, Rates of DCVG formation in rat kidney cel ls and kidney subcellular fractions were 5- to 20-fold lower than thos e in rat hepatocytes and liver subcellular fractions. Rates of DCVG fo rmation in kidney cells and subcellular fractions were comparable in m ale and female rats with the exception of male rat kidney microsomes, where DCVG formation was below the limit of detection, and those in li ver cells and subcellular fractions were >3-fold higher in male rats t han in female rats, Rates of DCVG formation in mouse kidney subcellula r fractions were approximately 10-fold higher than in corresponding fr actions from the rat, whereas those in mouse liver subcellular fractio ns were 4- to 8-fold higher than in corresponding rat tissues, with ra tes in male mouse liver cytosol and microsomes being modestly higher t han in corresponding fractions from female mice. GGT activity was bare ly detectable in livers, was about 20-fold higher in rat kidneys than in mouse kidneys, and was slightly higher in female rat kidneys than i n male rat kidneys, GST activity with 1-chloro-2,4-dinitrobenzene as s ubstrate exhibited tissue-, sex-, and species-dependent patterns that were generally similar to those with Tri as the substrate, These resul ts suggest that the higher susceptibility to Tri-induced renal toxicit y of male rats as compared with female rats correlates with rates of D CVG formation. The high rates of DCVG formation in mice, however, indi cate that other factors, possibly including differences in activities of cysteine conjugate beta-lyase or N-acetyltransferase, may also be i mportant determinants of the susceptibility to Tri.