Covalent protein binding of vinyl chloride metabolites during co-incubation of freshly isolated hepatocytes and hepatic sinusoidal cells of rats.
Proteins of isolated rat hepatic sinusoidal cells incubated with 14C-vinyl chloride, rat liver microsomes and an NADPH-regenerating system were alkylated by vinyl chloride metabolites formed by microsomes. This suggests that reactive vinyl chloride metabolites can penetrate sinusoidal cells. Protein alkylation in isolated hepatic sinusoidal cells was higher when these were co-incubated with isolated hepatocytes, indicating that reactive vinyl chloride metabolites formed by hepatocytes are stable enough to diffuse out of hepatocytes into sinusoidal cells. Glutathione added to the incubation medium inhibited the covalent protein binding of vinyl chloride metabolites in sinusoidal cells as well as in hepatocytes incubated separately and deleted the increased protein binding in sinusoidal cells co-incubated with hepatocytes. The data indicate that glutathione present in the incubation medium traps reactive vinyl chloride metabolites formed by hepatocytes which otherwise would react with cell constituents of sinusoidal cells. If similar conditions exist in vivo, the alkylation of DNA of liver endothelial cells by vinyl chloride metabolites formed in hepatocytes is possible. This would explain the induction of hemangioendotheliomas of the liver by vinyl chloride.
D000478:Alkylation; D000818:Animals; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D009249:NADP / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D014752:Vinyl Chloride / Q000378:metabolism*; D014753:Vinyl Compounds / Q000378:metabolism*
D014753:Vinyl Compounds; D009249:NADP; D005978:Glutathione; D014752:Vinyl Chloride