Fatty Acid β-Oxidation-Dependent Bioactivation of 5,6-Dichloro-4-Thia-5-Hexenoate and Analogs in Isolated Rat Hepatocytes

Abstract

S-(1,2-Dichlorovinyl)-L-cysteine (DCVC) is a nephrotoxic agent found in trichloroethene-extracted soybean meal (McKinney et al., 1957). Structure-toxicity studies with DCVC showed that the decarboxylated analog S-(1,2-dichlorovinyl)cysteamine was nontoxic whereas the desamino analog 5,6-dichloro-4-thia-5-hexenoate (DCTH) was a potent inhibitor of mitochondrial respiration (Parker et al., 1965; Stonard et al., 1977). The bioactivation mechanism of DCVC has been elucidated (Anders et al., 1988), but the bioactivation mechanism of DCTH has, however, not been defined. The objective of the present study was to elucidate the bioactivation mechanism of DCTH. This research tested the hypothesis that DCTH is bioactivated by enzymes of the fatty acid β-oxidation pathway to cytotoxic intermediates (Fig. 1). Specifically, DCTH may be metabolized by fatty acid acylCoA synthetase to the corresponding CoA thioester 1, which may be metabolized by fatty acid acyl-CoA dehydrogenase to 5,6-dichloro-4-thia-2,5-hexadienoate 2. Dienoate 2 may be metabolized by enoyl-CoA hydratase to the hemimercaptal 5,6-dichloro-4-thia-3-hydroxy-5-hexenoate 3, which may eliminate the unstable enethiol 1,2-dichloroethenethiol 4 whose formation is associated with the toxicity of DCVC (Anders et al., 1988).