Ethanol Oxidation and Toxicity: Role of Alcohol P‐450 Oxygenase

Abstract

The isolation and characterization of ethanol-inducible rabbit liver microsomal cytochrome P-450, termed P-450 3a or P-450ALC, has provided definitive evidence for the role of this enzyme in alcohol oxidation. From findings on the distribution, substrate specificity, and mechanism of action of P-450ALC we have suggested "alcohol P-450 oxygenase" as a more biochemically accurate name than "microsomal ethanol-oxidizing system." The present review is concerned with studies in this and other laboratories on activities and inducers associated with this versatile enzyme. Numerous xenobiotics, including alcohols and ketones, nitrosamines, aromatic compounds, and halogenated alkanes, alkenes, and ethers, are known to undergo increased microsomal metabolism after chronic exposure of various species to ethanol. Diverse compounds and treatments may induce P-450ALC, including the administration of ten or more chemically different compounds, fasting, or the diabetic state. Whether a common mechanism of induction is involved is unknown at this time. As direct evidence that P-450ALC catalyzes numerous metabolic reactions, the purified rabbit enzyme has been used in a reconstituted system to demonstrate various metabolic transformations, including the oxidation of various alcohols, acetone, acetol, p-nitrophenol, and aniline, the dealkylation of substituted nitrosamines, the reductive dechlorination of carbon tetrachloride, carbon tetrachloride-induced lipid peroxidation, and acetaminophen activation to form the glutathione conjugate.