FORMATION OF GSH-DERIVATIVES AS A PATHWAY FOR INACTIVE INTERMEDIATES IN VINYLIDENE CHLORIDE-TREATED RATS

The two conjugates, S-[N-(2-hydroxyethyl)carbamoylmethyl] glutathione (GSAAE), and its corresponding mercapturic derivative etyl-S-[N-(2-hyd roxyethyl)carbamoylmethyl]cysteine (NCySAAE) were administered to fast ed Sprague-Dawley rats as putative metabolites of vinylidene chloride (VDC). Methylthioacetylaminoethanol (MAAE) was identified in the urine of GSAAE- or NCySAAE-treated rats (0.5-2.0 mmol/kg, i.p.), as well as in the urine of VDC-treated rats (0.5-2.0 mmol/kg, p.o.). The effects of VDC, GSAAE and NCySAAE On the kidney and liver were also examined using aspartate aminotransferase (ASAT), N-acetyl-beta-D-glucosaminida se (NAG) and beta(2)-microglobulin (beta(2)-m) as urinary parameters o f nephrotoxicity, and glutamate dehydrogenase (GLDH), sorbitol dehydro genase (SDH) and alanine aminotransferase (ALAT) as serum parameters o f hepatotoxicity. Unlike treatment with VDC, treatment with both GSAAE and NCySAAE failed to cause kidney and liver toxicity. The results su pport the hypothesis that MAAE originates from the formation of GSAAE and further metabolization to NCySAAE, and that MAAE excretion does no t reveal a pathway of reactive intermediates.