Potentiation of fluroxene (2,2,2-trifluoroethyl vinyl ether) toxicity with polychlorinated biphenyls

Abstract

The effects of induction of rat hepatic microsomal cytochrome P-450 by commercial mixtures of polychlorinated biphenyls (PCBs) (100 mg/kg/day for 3 days) in potentiating the toxicity of the anesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether) have been determined. The PCB mixtures used were Aroclors 1221, 1016, 1254, and 1260. All Aroclors significantly induced cytochrome P-450 relative to controls (1.4–2.1), and the more highly chlorinated PCB mixtures produced the greatest induction. The cytochrome P-450 composition of the Aroclor-induced microsomes was probed using R warfarin metabolism. Aroclor 1254-induced microsomes comprised mainly cytochrome P-448 of the 3-methylcholanthrene-inducible type, and Aroclor 1260-induced microsomes comprised mainly cytochrome P-450 of the phenobarbital-inducible type, although each contained lesser quantities of the other forms. Only Aroclor 1254 and 1260 induction produced death in rats (12/20 and 11/13 respectively) following ip administration of fluroxene (2.5 g/kg body wt). Fluroxene potentiated the destruction of cytochrome P-450 in vivo and this destruction was enhanced by Aroclor induction. Cytochrome P-448 suffered the greatest destruction in Aroclor 1221- and 1254-induced microsomes, and cytochrome P-450 was most extensively destroyed in Aroclor 1260-induced microsomes. The Aroclor 1254-induced cytochrome P-450 concentration did not return to the corresponding control value 24 hr after clearance of the fluroxene dose which implies that fluroxene metabolism interferes with the biosynthesis of cytochrome P-450. It is concluded that some Aroclors, through induction of cytochrome P-450 of the phenobarbital-inducible type, increase the rates of metabolism of fluroxene, which results in the production of toxic metabolites leading to liver necrosis, destruction of cytochrome P-450, and death.