Chronic intragastric infusion of ethanol-containing diets induces CYP3A9 while decreasing CYP3A2 in male rats

The CYP3A subfamily is the most abundant of the human hepatic cytochrome P4 50 enzymes. They mediate the biotransformation of many drugs, including a n umber of psychotropic, cardiac, analgesic, hormonal, immunosuppressant, ant ineoplastic, and antihistaminic agents. We studied diet/ethanol interaction s using total enteral nutrition in adult male Sprague-Dawley rats with diet s containing 16% protein, ethanol (13 g/kg), corn oil (fat; 25-45%), and ca rbohydrate (CHO; 1-21%). Using this model, chronic ethanol feeding decrease d CYP3A activity (testosterone 6 beta -hydroxylation) and apoprotein levels (Western blot) (P<.05) and these effects were independent of the dietary C HO/fat ratio. The CYP3A2 mRNA levels decreased (P<.05) in the rats fed etha nol-containing diets by 73 to 83% compared with rats fed control diets, reg ardless of the CHO/fat ratio. In contrast, ethanol induced CYP3A9 mRNA leve ls (P<.05) and this effect was greater (P<.05) in the high-CHO/lowfat group (11.3-fold) than in the low-CHO/high-fat group (2.6-fold). Purified recomb inant rat P450 3A9 had a chlorzoxazone 6-hydroxylase activity with a turnov er number 1.3 nmol/min/nmol of P450. These results indicate that 1) ethanol differentially affects the expression of CYP3A gene family and this regula tion appears to be modulated by dietary CHO/fat ratio; 2) the decrease in t estosterone 6 beta -hydroxylase activity and CYP3A apoprotein levels are mo st 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.