Contrasting effects of 1,1,1-trichloroethane on [14C]vinyl chloride metabolism and activation in hepatic microsomes from phenobarbital- and isoniazid-treated rats.
The interaction of 1,1,1-trichloroethane (TCE), a widely used chlorocarbon solvent, on the metabolism and activation of [14C]-vinyl chloride in rat hepatic microsomes was investigated to determine the effects of combined exposures to these compounds. In microsomes from phenobarbital (PB)-treated rats, TCE increased vinyl chloride-protein binding and vinyl chloride aqueous metabolite formation over twofold when vinyl chloride 0.32% (v/v) and TCE (0.65%) are incubated together. In contrast, under similar incubation conditions, TCE inhibited vinyl chloride metabolism and protein binding up to 45% in microsomes from isoniazid-treated animals. TCE also inhibited vinyl chloride metabolism and binding in microsomes from untreated rats, but to a lesser degree. Like the effect of TCE on vinyl chloride-protein binding, TCE increased vinyl chloride binding to DNA approximately 130% in microsomes from PB-treated rats, yet inhibited vinyl chloride-DNA binding in microsomes from isoniazid-treated and untreated animals. Consistent with TCE effects on vinyl chloride binding and aqueous metabolite production, TCE further increased cytochrome P450 loss due to vinyl chloride metabolism in microsomes from PB-treated rats, but was inhibitory to cytochrome P450 loss due to vinyl chloride metabolism in microsomes from isoniazid-treated and untreated rats. These data demonstrate that the relatively metabolically inert solvent, 1,1,1-trichloroethane, can directly increase vinyl chloride metabolism and activation catalyzed by the phenobarbital-inducible isozymes, but is inhibitory toward vinyl chloride metabolism catalyzed by the isoniazid-inducible CYP2E1.
Baker
M T
MT
Department of Anesthesia, University of Iowa, Iowa City 52242.
Ronnenberg
W C
WC
D000818:Animals; D001665:Binding Sites; D001711:Biotransformation / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004347:Drug Interactions; D007527:Isoenzymes / Q000378:metabolism; D007538:Isoniazid / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014240:Trichloroethanes / Q000633:toxicity*; D014752:Vinyl Chloride / Q000378:metabolism* / Q000633:toxicity
D007527:Isoenzymes; D014240:Trichloroethanes; C024566:1,1,1-trichloroethane; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D002374:Catalase; D007538:Isoniazid; D014752:Vinyl Chloride; D010634:Phenobarbital