SPECIES-RELATED AND SEX-RELATED DIFFERENCES IN METABOLISM OF TRICHLOROETHYLENE TO YIELD CHLORAL AND TRICHLOROETHANOL IN MOUSE, RAT, AND HUMAN LIVER-MICROSOMES

Trichloroethylene (TRI) has been shown to cause a variety of tumors, p articularly in mouse liver and lung and rat kidney. However, a clear a ssociation between exposure to TRI and cancer development in humans ha s not been established. Because TRI metabolism by cytochrome P450s has been implicated in the mechanisms of TRI-induced carcinogenicity in m ice, the purpose of the present study was to characterize the kinetics of TRI oxidation in male and female mouse, rat, and human liver micro somes to possibly allow for a better assessment of human risk. Methods were developed to detect and quantitate chloral, trichloroethanol, tr ichloroacetic acid, dichloroacetic acid, chloroacetic acid, glyoxylic acid, and oxalic acid, known TRI metabolites in rodents or humans. How ever, only chloral and its further metabolite, trichloroethanol, were consistently detected in the various liver microsomes in the presence of NADPH. Chloral was the major metabolite detected, and its levels we re species- and sex-dependent; the amounts of trichloroethanol detecte d were also species- and sex-dependent but never exceeded 15% of total metabolites. Double-reciprocal plots of metabolite formation with mal e and female rat and human liver microsomes indicated biphasic kinetic s, but this trend was not observed with microsomes from male or female mouse liver. The V-max data are consistent, with male and female mice being more susceptible to TRI-induced liver carcinogenicity than male rats. However, the V-max/K-m ratios in male and female rat liver micr osomes, in comparison with the male mouse liver microsomes, did not co rrelate with tumor incidences in these tissues. Furthermore, as only t wo out of six human liver samples examined exhibited V-max/K-m ratios similar or higher than the ratio obtained with male mouse liver, human s may vary in their toxic response after TRI exposure.