Baker M T, Ronnenberg W C
Department of Anesthesia, University of Iowa, Iowa City 52242.
Toxicol Appl Pharmacol. 1993 Mar;119(1):17-22. doi: 10.1006/taap.1993.1039.
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.
研究了广泛使用的氯代烃溶剂1,1,1 - 三氯乙烷（TCE）对大鼠肝微粒体中[14C] - 氯乙烯代谢和活化的相互作用，以确定这些化合物联合暴露的影响。在苯巴比妥（PB）处理的大鼠的微粒体中，当0.32%（v/v）的氯乙烯与TCE（0.65%）一起孵育时，TCE使氯乙烯 - 蛋白质结合以及氯乙烯水性代谢物的形成增加了两倍多。相比之下，在类似的孵育条件下，TCE在异烟肼处理的动物的微粒体中抑制氯乙烯代谢和蛋白质结合高达45%。TCE在未处理大鼠的微粒体中也抑制氯乙烯代谢和结合，但程度较小。与TCE对氯乙烯 - 蛋白质结合的影响类似，TCE使PB处理的大鼠的微粒体中氯乙烯与DNA的结合增加了约130%，但在异烟肼处理和未处理的动物的微粒体中抑制氯乙烯与DNA的结合。与TCE对氯乙烯结合和水性代谢物产生的影响一致，TCE进一步增加了PB处理的大鼠的微粒体中因氯乙烯代谢导致的细胞色素P450损失，但在异烟肼处理和未处理的大鼠的微粒体中抑制因氯乙烯代谢导致的细胞色素P450损失。这些数据表明，相对代谢惰性的溶剂1,1,1 - 三氯乙烷可直接增加由苯巴比妥诱导的同工酶催化的氯乙烯代谢和活化，但对由异烟肼诱导的CYP2E1催化的氯乙烯代谢具有抑制作用。
