Role of hepatic microsomal cytochrome P-450 in the toxicity of fluorinated ether anesthetics

To evaluate the role of cytochrome P-450 in anesthetic toxicity, we investigated the effects of hepatic microsomal cytochrome P-450 inducers phenobarbital (PB), 3-methylcholanthrene (3-MC) and pregnenolone-16 α-carbonitrile (PCN)] and inhibitors SKF 525-A, metyrapone, and 2allyl2isopropylacetamide (ALA)] on the potentiation of lethal effects to rats of i.p. administered 2,2,2-trifluoroethyl vinyl ether (TFVE), ethyl 2,2,2-trifluoroethyl ether (TFEE), allyl 2,2,2-trifluoroethyl ether (TFAE) and 2,3-epoxypropyl 2,2,2-trifluoroethyl ether (EPTFE). The time courses of tail-vein blood anesthetic concentrations and quantities of exhaled anesthetics together with the in vitro metabolism of the anesthetics and their binding to microsomal cytochromes P-450 were also determined. The results indicate that (1) the majority of the administered anesthetics make a single pass through the liver prior to exhalation and apparently are metabolized to toxic products, (2) the epoxide (EPTFE) exerts its lethal effects independently of cytochrome P-450 catalyzed metabolism and does not lie on the major path of TFAE metabolism, (3) all the anesthetics yield 2,2,2-trinuoroethanol (TFE) on metabolism in vitro but lethality does not always correlate with the rates of TFE formation, (4) PB induced cytochromes P-450 potentiate lethal effects of TFVE and TFEE but not of TFAE, and inhibitors differentiate mechanisms of TFVE and TFEE lethality, (5) PCN induced cytochromes P-450 potentiate the toxicity of TFVE, TFAE, and TFEE in a similar manner, and (6) 3-MC induction potentiates TFEE and TFAE lethality apparently independently of cytochrome P-450 catalyzed metabolism.