The Effect of Ethanol Administration on Drug Oxidations and Possible Mechanism of Ethanol-Barbiturate Interactions

Abstract

Chronic administration of ethanol to rats has no effect on the plasma half life of pentobarbitone, which indicates that ethanol does not induce the microsomal enzyme system and that the latter is therefore not identical with the 'microsomal ethanol oxidizing system'. The microsomal oxidation of ethanol observed in vitro is probably the result of metabolism of ethanol by contaminating alcohol dehydrogenase and by catalase peroxidation. Chronic administration of ethanol to rats leads to stimulation of the activity of the hepatic drug metabolizing enzymes in vitro which is not paralleled by any corresponding increase in the concentration of cytochrome P-450, the terminal enzyme in the microsomal mono oxygenase system. However, no changes were seen in hexobarbital sleeping time or zoxazolamine paralysis time, confirming that ethanol pretreatment does not lead to any significant stimulation of the hepatic microsomal drug metabolizing enzymes in vivo. The observed inhibition of barbiturate metabolism after simultaneous administration of large amounts of ethanol may be attributed to nonspecific interaction with the active site of the microsomal drug metabolizing enzymes. Ethanol has also been shown to potentiate the enzyme induction effect of phenobarbitone in vitro in respect of cytochrome P-450 and cytochrome b5. The effect was even more pronounced in vivo when none of the animals pretreated with both phenobarbitone and ethanol exhibited zoxazolamine paralysis and only one third of these animals exhibited narcosis after hexobarbitone administration. The lipophilic character of ethanol allows it to penetrate the lipid environment of the endoplasmic reticulum and to interact with cytochrome P-450 giving a type II substrate interaction spectrum, although it is not metabolized by the microsomal mono oxygenase system. The molar concentration of ethanol required to give a type II spectrum is much higher than that required for aniline suggesting that the interaction of ethanol with cytochrome P-450 is a non specific interaction with the lipophilic phase of the microsomal membrane adjacent to the haemoprotein. Ethanol may therefore act as an activator of the microsomal mono oxygenase enzyme system either by modification of the membrane environment, by allosteric effects, or by displacement of other endogenous or exogenous substrates already bound to the enzymic sites. The potentiation of phenobarbitone induction of this enzyme system may be the result of stabilization of the substrate enzyme complex, as it has been suggested that induction of the microsomal enzymes is a function of the stability of the enzyme substrate complex.