Chronic Intragastric Infusion of Ethanol-Containing Diets Induces CYP3A9 While Decreasing CYP3A2 in Male Rats

• Published in: The Journal of pharmacology and experimental therapeutics 2000-11, Vol.295 (2), p.747-752
• Main Authors: Rowlands, J C, Wang, H, Hakkak, R, Ronis, M J, Strobel, H W, Badger, T M
• Format: Article
• Language: English
• Subjects: Animals; Aryl Hydrocarbon Hydroxylases; Central Nervous System Depressants - pharmacology; Chlorzoxazone - pharmacology; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Diet; Dietary Carbohydrates - pharmacology; Dietary Fats - pharmacology; Enteral Nutrition; Enzyme Induction - drug effects; Ethanol - pharmacology; Isoenzymes - biosynthesis; Isoenzymes - genetics; Isoenzymes - metabolism; Male; Oxidoreductases, N-Demethylating - biosynthesis; Oxidoreductases, N-Demethylating - genetics; Oxidoreductases, N-Demethylating - metabolism; Rats; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Steroid Hydroxylases - biosynthesis; Steroid Hydroxylases - metabolism; Substrate Specificity
• ISSN: 0022-3565; 1521-0103

The CYP3A subfamily is the most abundant of the human hepatic cytochrome P450 enzymes. They mediate the biotransformation of many drugs, including a number of psychotropic, cardiac, analgesic, hormonal, immunosuppressant, antineoplastic, and antihistaminic agents. We studied diet/ethanol interactions using total enteral nutrition in adult male Sprague-Dawley rats with diets containing 16% protein, ethanol (13 g/kg), corn oil (fat; 25–45%), and carbohydrate (CHO; 1–21%). Using this model, chronic ethanol feeding decreased CYP3A activity (testosterone 6β-hydroxylation) and apoprotein levels (Western blot) ( P < .05) and these effects were independent of the dietary CHO/fat ratio. The CYP3A2 mRNA levels decreased ( P < .05) in the rats fed ethanol-containing diets by 73 to 83% compared with rats fed control diets, regardless of the CHO/fat ratio. In contrast, ethanol induced CYP3A9 mRNA levels ( P < .05) and this effect was greater ( P < .05) in the high-CHO/low-fat group (11.3-fold) than in the low-CHO/high-fat group (2.6-fold). Purified recombinant rat P450 3A9 had a chlorzoxazone 6-hydroxylase activity with a turnover number 1.3 nmol/min/nmol of P450. These results indicate that 1) ethanol differentially affects the expression of CYP3A gene family and this regulation appears to be modulated by dietary CHO/fat ratio; 2) the decrease in testosterone 6β-hydroxylase activity and CYP3A apoprotein levels are most likely due to the ethanol-induced decrease in CYP3A2 mRNA levels; and 3) CYP3A9 is induced by ethanol and is a low-affinity, high- K m chlorzoxazone hydroxylase.