Chronic intragastric infusion of ethanol-containing diets induces CYP3A9 while decreasing CYP3A2 in male rats
| Autor: | J C, Rowlands, H, Wang, R, Hakkak, M J, Ronis, H W, Strobel, T M, Badger |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Ethanol Central Nervous System Depressants Oxidoreductases N-Demethylating Dietary Fats Diet Rats Substrate Specificity Isoenzymes Rats Sprague-Dawley Chlorzoxazone Enteral Nutrition Cytochrome P-450 Enzyme System Enzyme Induction Steroid Hydroxylases Dietary Carbohydrates Animals Cytochrome P-450 CYP3A Aryl Hydrocarbon Hydroxylases RNA Messenger |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 295(2) |
| ISSN: | 0022-3565 |
| Popis: | 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 6 beta-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 6 beta-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. |
| Databáze: | OpenAIRE |
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