SPECIES-DIFFERENCES IN THE BIOTRANSFORMATION OF ETHYL CHLORIDE .2. GSH-DEPENDENT METABOLISM

Groups of male and female F-344 rats and B6C3F1 mice were exposed to 1 5 000 ppm ethyl chloride (monochloroethane, ECL) or to air for 5 days (6 h/day). In this report, features of GSH-dependent ECL metabolism in the animals are described. A concurrent report describes the features of the cytochrome P450-dependent oxidative ECL metabolism (Fedtke et al. 1994). ECL conjugation to GSH in hepatic cytosolic fractions was c atalyzed by GSH S-transferases. The specific activities were 0.16 +/- 0.03 and 0.17 +/- 0.01 nmol ECL conjugated/(min mg protein) in air tre ated male and female F-344 rats, respectively. These activities were n ot significantly altered by the ECL treatment. Compared with rats, the GSH-transferase activities towards ECL were generally higher in male and female B6C3F1 mice (0.71 +/- 0.19 and 1.01 +/- 0.19, respectively) and were slightly decreased by ECL treatment. The ECL conjugation to GSH resulted in a marked reduction of the GSH concentration in the lun g and the uterus after 5 days of exposure. In contrast, liver and kidn ey GSH concentrations were affected only to a minor degree. Formed S-e thyl-glutathione was converted to the mercapturic acid S-ethyl-N-acety l-L-cysteine (SENACys), which was detected in the urine of both specie s. In addition, the non-acetylated intermediate S-ethyl-L-cysteine (SE Cys) was excreted in mouse urine but not in rat urine. The cumulative amounts of SENACys and SECys excreted after 5 days were up to fivefold higher in mice than in rats and the excretion kinetics were species s pecific. The results are discussed with regard to a 2 year bioassay wi th F-344 rats and B6C3F1 mice exposed to 15 000 ppm ECL (NTP 1989). In this bioassay, a species specific carcinogenic response in the mouse uterus was observed. It is proposed that the mechanism of tumor induct ion is a high dose phenomenon and more likely related to the GSH conju gation than to the oxidative metabolism or to possible genotoxic effec ts of ECL or its metabolites.