Microsomal ethanol oxidizing system (MEOS): interaction with ethanol, drugs and carcinogens.
Several studies in our unit showed that in men, baboons, rats and deermice, blood ethanol clearance is significantly accelerated at ethanol concentrations higher than the levels needed to effectively saturate the low Km forms of ADH present in animals, thereby incriminating a high Km non-ADH system such as microsomal ethanol oxidizing system (MEOS). Furthermore, kinetics of blood ethanol clearance were consistent with the Km of MEOS. After chronic ethanol consumption, there was an increase in rates of ethanol elimination and in the activity of MEOS. There was an associated rise in microsomal cytochrome P-450, including a form (different from that of a non-ADH pathway of ethanol metabolism and its increase after chronic ethanol consumption was most conclusively shown in ADH-negative deermice. Microsomal induction was also associated with enhanced metabolism of other drugs, resulting in metabolic drug tolerance. In addition, there was increased activation of known hepatotoxic agents (such as CCl4 and acetaminophen) which may explain the enhanced susceptibility of alcoholics to the toxicity of solvents and commonly used drugs. There was enhanced activation of procarcinogens, sometimes at concentrations much lower than those required for other microsomal inducers. Moreover, catabolism of retinoic acid was accelerated possibly contributing to hepatic vitamin A depletion. In conclusion, after chronic ethanol consumption, enhanced MEOS activity and concomitant cytochrome P-450 changes may contribute to accelerated ethanol and drug metabolism and associated activation of hepatotoxic agents and carcinogens.
D000079:Acetaldehyde / Q000097:blood; D000426:Alcohol Dehydrogenase; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000437:Alcoholism / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004361:Drug Tolerance; D064420:Drug-Related Side Effects and Adverse Reactions; D000431:Ethanol / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D008658:Inactivation, Metabolic; D008862:Microsomes, Liver / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010713:Phosphatidylcholines / Q000378:metabolism; D011817:Rabbits; D051381:Rats
D002273:Carcinogens; D010713:Phosphatidylcholines; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D000429:Alcohol Oxidoreductases; D000426:Alcohol Dehydrogenase; D002374:Catalase; D009251:NADPH-Ferrihemoprotein Reductase; D000079:Acetaldehyde