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The interaction of hepatic microsomal cytochrome P-450 with fluroxene (2,2,2-trifluoroethyl vinyl ether) in vitro

Biochemical Pharmacology
Publication Date
DOI: 10.1016/0006-2952(76)90146-5
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Abstract The anaesthetic agent fluroxene (2,2.2-trifluoroethyl vinyl ether) and a closely related compound 2,2,2-trifluoroethyl ethyl ether (TFEE) interact with the cytochromc P-450 component of isolated rat hepatic microsomcs to produce a type I difference spectrum. The extent of the absorbance difference ( ΔA) between λ max (390 nm) and λ min (420 nm) produced with fluroxene or TFEE is dependent on the concentration of the anaesthetic agent and the extent and type of prior induction of the microsomes. Induction of cytochrome P-448 with 3-methylcholanthrene (MC) or 3.4-benzpyrene (BP) does not affect the magnitude of the maximal absorbance difference spectrum ( ΔA max) relative to uninduced microsomes. In contrast, phenobarbital (PB) induced microsomes exhibit ΔA max values with either anaesthetic agent which, relative to controls, arc increased approximately in proportion to the increase in the level of total type P-450 cytochromes. The K s values for the binding of fluroxene and TFFE to all microsomal preparations are 9.3 × 10 4 M and 1.7 × 10 −3 respectively. Both anaesthetics are metabolized by hepatic microsomal cytochrome P-450 as evidenced by enhanced carbon monoxide-inhibitahic NADPH oxidation in the presence of these compounds. The maximum velocities of NADPH consumption in the presence of cither anaesthetic are unaffected by induction with BP or MC but are increased approximately 3-fold following induction of cytochrome P-450 with PB. For fluroxene metabolism by all microsomes K m was determined to be 8.4 × 10 4 M. Determination of K m values for TFEE metabolism is more complex as biphasic effects are observed with some systems. We conclude that fluroxene and TFEE bind to cytochrome P-450 and are metabolized but that TFEE is a poorer substrate. In contrast cytochrome P-448 neither binds nor metabolizes either anaesthetic. Since K m and K s values for fluroxene are the same we conclude that the rate-limiting step of its metabolism occurs at a step after the binding of fluroxene to ferricytochrome P-450.

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