Fluroxene (2,2,2-trifluoroethyl vinyl ether) mediated destruction of cytochrome P-450 in vitro

Abstract

Incubation of rat hepatic microsomes with an NADPH generating system and the anaesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether) at 30° resulted in the destruction of hepatic cytochrome P-450 in excess of that observed in the presence of the NADPH generating system alone. The extent of destruction of cytochrome P-450 was markedly enhanced by pre-induction of cytochrome P-450 with phenobarbital. Induction with 3-methylcholanthrene or 3,4-benzpyrene, which induce cytochrome P-448, enhanced the overall level of cytochrome destruction. No destruction was observed when CO was added to the system prior to the addition of the anaesthetic, or when NADH replaced NADPH or when fluroxene was replaced by its chemically reduced from, 2,2,2-trifluoroethyl ethyl ether. The fluorexene potentiated destruction of cytochrome P-450 was accompanied by the loss of heme from the microsomes but not by the appearance of cytochrome P-420 nor by the loss of cytochrome b 5 or NADPH-cytochrome c reductase. We conclude that cytochrome P-450 is specifically destroyed by fluroxene in a metabolic process involving destruction of its heme group. The vinyl group of the anaesthetic is essential for the destructive process.