Further investigations of the metabolism of fluroxene and the degradation of cytochromes p-450 in vitro

Abstract

The effects of inhibitors and of inducing agents for cytochromes P-450 on the fluroxene mediated destruction of cytochromes P-450 were investigated with hepatic microsomes from male rats in vitro and compared with the metabolism of fluroxene (2,2,2-trifluoroethyl vinyl ether) to 2,2,2-tri-fluoroethanol under similar conditions. The fluroxene mediated destruction of cytochromes P-450 and the metabolism of fluroxene are fully inhibited under totally anaerobic conditions. Carbon monoxide, SKF 525A and metyrapone fully inhibit the fluroxene mediated destruction of cytochromes P-450 and partially inhibit the metabolism of fluroxene to trifluoroethanol in microsomes from phenobarbital pretreated rats. The K m values for the destruction of cytochromes P-450 by fluroxene in vitro were calculated as 0.8, 3.3 and 1.5 mM for microsomes from phenobarbital induced, 3-methylcholanthrene induced and uninduced animals, respectively. V max values for 3-methylcholanthrene and phenobarbital induced microsomes (approximately 0.5 nmol cytochromes P-450 destroyed/mg microsomal protein/7 min) are elevated compared to uninduced microsomes (0.2 nmol cytochromes P-450 destroyed/mg microsomal protein/10 min). The K m value for the metabolism of fluroxene to trifluoroethanol in control microsomes of approximately 1.0 mM is unchanged following induction, and V max for the production of trifluoroethanol is increased relative to controls only in phenobarbital induced microsomes. It is concluded that the fluroxene mediated destruction of cytochromes P-450 appears to involve both cytochrome P-448 and cytochrome P-450 whereas the production of trifluoroethanol from fluroxene is catalyzed by cytochrome P-450 but not by cytochrome P-448.