Binding kinetics of vinyl chloride and vinyl bromide at very low doses.
Vinyl chloride and vinyl bromide are metabolically activated by liver microsomal enzymes to intermediates that covalently bind to proteins and nucleic acids. Several lines of evidence suggest the involvement of the epoxides, i.e., chloroethylene oxide or bromoethylene oxide. Proven targets for alkylation are adenine, cytosine and guanine moieties in nucleic acids, and sulfhydryl groups of proteins. For all the halogenated ethylenes studied so far, including vinyl chloride and vinyl bromide, metabolism in vivo is a dose-dependent, saturable process. The metabolic capacity of rats is saturated at atmospheric concentrations of 250 ppm vinyl chloride and 55 ppm vinyl bromide. As recent reports describe a diminishment of hepatocellular glutathione in rats after exposure to vinyl chloride concentrations of 50 ppm and more, we carried out a series of experiments measuring covalent binding of vinyl chloride metabolites after exposure to different concentrations of 14C-vinyl chloride. In all of these experiments, including one of an exposure to only 2 ppm vinyl chloride, hepatic covalent protein binding was related to the dose of vinyl chloride which was actually metabolized, and the ratio between bound and metabolized material was constant. This strongly suggests that hepatic glutathione levels must have only a very limited impact on covalent protein binding of vinyl chloride metabolites, an assumption which is supported by a lacking effect of a pretreatment with diethylmaleate. A scheme of hepatocellular compartimentation of metabolic steps is proposed which serves to explain these findings.
D000478:Alkylation; D000818:Animals; D005978:Glutathione / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D014018:Tissue Distribution; D014752:Vinyl Chloride / Q000378:metabolism*; D014753:Vinyl Compounds / Q000378:metabolism*
D014753:Vinyl Compounds; C003763:vinyl bromide; D005978:Glutathione; D014752:Vinyl Chloride