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Destruction of highly purified cytochromes P-450 associated with metabolism of fluorinated ether anesthetics

1981; Elsevier BV; Volume: 212; Issue: 2 Linguagem: Inglês

10.1016/0003-9861(81)90376-3

1096-0384

Michael J. Murphy, Deborah Dunbar, F. Peter Guengerich, Laurence S. Kaminsky,

Cancer, Hypoxia, and Metabolism

Abstract Destruction of highly purified hepatic cytochromes P -450 PB-B and BNF-B, the major forms from phenobarbital (PB)- or β-naphthoflavone (BNF)-induced rats, and of microsomal cytochromes P -450 from PB-induced rats—in the course of metabolism of the anesthetics 2,2,2-trifluoroethyl vinyl ether, 2,2,2-trifluoroethyl ethyl ether, 2,2,2-trifluoroethyl allyl ether, and ethyl vinyl ether—has been investigated. Such destruction is important for the control of cytochrome P -450 activities and for drug-drug interactions. The following conclusions have been drawn from the results: Destruction of cytochromes P -450 is dependent on NADPH-mediated metabolism of the anesthetics. Both purified cytochromes in reconstituted systems are more susceptible to destruction than microsomal membrane-bound cytochromes P -450. Cytochrome P -450 BNF-B is more susceptible to destruction than cytochrome P -450 PB-B. 2,2,2-Trifluoroethyl vinyl ether-mediated destruction probably results from epoxidation and subsequent carbonium ion formation and not from its metabolites, 2,2,2-trifluoroethanol and glycolaldehyde. Some of the 2,2,2-trifluoroethyl allyl ether-mediated destruction possibly results from the destructive properties of the metabolite, acrolein. Unsaturated carbon-carbon bonds are essential for destruction directly or else possibly indirectly after incorporation into metabolites. Fluorine substituants do not affect destruction of purified cytochromes P -450 but enhance destruction of microsomal cytochromes, possibly by facilitating accessibility.