Differential effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism in the rat.
The effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism have been studied both in vivo and in vitro in the rat, using caffeine, phenacetin, antipyrine and aminopyrine as test substrates. N-Demethylation of aminopyrine (P-450 mediated) was increased both in vivo and in vitro in rats after chronic ethanol feeding (P less than 0.05) whereas in vivo N-demethylation of caffeine and O-dealkylation of phenacetin (P-448 mediated) were unchanged in the same animals. N-Demethylation of antipyrine was increased by both phenobarbital and 3-methylcholanthrene pretreatment and by chronic ethanol feeding (P less than 0.05), possibly due to cytochrome P-450 induction. Furthermore, the Michaelis affinity constants, Km, for hepatic microsomal aminopyrine N-demethylase and antipyrine N-demethylase were lower in chronic ethanol-fed animals (P less than 0.05), suggesting a qualitative change in the enzymes resulting in greater substrate affinity. These findings suggest a differential effect of chronic ethanol feeding on the induction of cytochrome P-450- and cytochrome P-448 mediated drug metabolism, with a greater effect on the former microsomal system.
D000633:Aminopyrine N-Demethylase / Q000032:analysis; D000818:Animals; D000983:Antipyrine / Q000378:metabolism; D001580:Benzopyrenes / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D003580:Cytochromes / Q000502:physiology*; D004790:Enzyme Induction; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D066298:In Vitro Techniques; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D001580:Benzopyrenes; D003580:Cytochromes; D004364:Pharmaceutical Preparations; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D000633:Aminopyrine N-Demethylase; D000983:Antipyrine