Formation and inactivation of a chemically reactive metabolite of vinyl chloride

Abstract

The mechanisms responsible for, and protecting against, metabolic activation of vinyl chloride were investigated in the rat. When [ 14C]vinyl chloride was incubated with hepatic microsomes, a 14C-labeled material became irreversibly bound to microsomal proteins; binding required NADPH, was decreased by CO, SKF 525-A, or glutathione, and was increased by 1,1,1-trichloropropene-2,3-oxide (TCPO). Inhalation of a 5% vinyl chloride atmosphere decreased hepatic cytochrome P-450 and glutathione. Pretreatment of the animals with DDT or phenobarbital (1) increased in vitro irreversible binding to microsomal proteins measured in the presence, but not in the absence, of TCPO and increased the in vivo loss of cytochrome P-450 during inhalation of vinyl chloride, but (2) decreased the in vitro irreversible binding to 10,000 g supernatant proteins and the in vivo loss of glutathione during inhalation of vinyl chloride. These results are consistent with the views that (1) vinyl chloride is activated by cytochrome P-450 into its chemically reactive epoxide, (2) the epoxide may be inactivated by epoxide hydrase or by binding to glutathione, (3) pretreatment with DDT or phenobarbital increases both the formation rate of the epoxide and its inactivation rate by epoxide hydrase, and (4) cytochrome P-450 destruction is related to the formation rate of the expoxide, whereas glutathione depletion seems related to only that fraction of the formed epoxide which has escaped inactivation by microsomal epoxide hydrase and has diffused in the cytosol.