EFFECT OF CYTOCHROME-P450 ISOZYME INDUCTION AND GLUTATHIONE DEPLETIONON THE METABOLISM OF CS2 TO TTCA IN RATS

Analysis of 2-thiothiazolidine-4-carboxylic acid (TTCA), a metabolite of carbon disulfide (CS2), is used in the biological monitoring exposu re to CS2 at work. In order to clarify the metabolic reasons for indiv idual variation in the urinary excretion of TTCA, the latter was studi ed in rats pretreated with model cytochrome P450 (CYP) enzyme inducers or glutathione (GSH) depletors. Ethanol, phenobarbital (PB) or 3-meth ylcholanthrene (MC) did not increase 24-h TTCA output following CS2 in halation (50 or 500 ppm, 6 h). After oral dosing (10 mg/rat), PB had a n inhibiting effect on the excretion rate of TTCA. Tissue GSH depletor s phorone, L-buthionine-(RS)-sulfoximine (BSO) and diethylmaleate (DEM ) decreased TTCA excretion in rats given an oral dose (10 mg/rat) of C S2. The initial inhibition by phorone and DEM was reversed after 6 h a nd from 12 h onward the TTCA in urine exceeded the control level, an e ffect not seen with BSO. The proportion of CS2 excreted in urine as TT CA within 24 h was 1.7% in control rats and 1% after BSO treatment, 1. 3% after PB, 1.7% after acetone, 1.8% after MC, 2.0% after phorone and 2.5% after DEM treatment. The amount of TTCA in urine increased with the CS2 dose in a nonlinear fashion: 1.6 mu mol (50 ppm/6 h) vs. 4.9 m u mol (500 ppm/6 h), and 0.2 mu mol (1 mg/kg) versus 3.6 mu mol (100 m g/kg). It is concluded that induction of different cytochrome P450 iso forms and transient glutathione depletion have only minor effects on t he disposition of TTCA in rats following low-level CS2 exposure persis tently low glutathione level as achieved by E.G. BSO, markedly decreas ed the metabolism of CS2 to TTCA; these metabolic effecters are unlike ly-to have a major role in the individual variation of CS2 metabolism in exposed workers.