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Vol. 295, Issue 2, 747-752, November 2000

Chronic Intragastric Infusion of Ethanol-Containing Diets Induces CYP3A9 While Decreasing CYP3A2 in Male Rats1,2

J. Craig Rowlands, Huamin Wang, Reza Hakkak, Martin J. J. Ronis, Henry W. Strobel and Thomas M. Badger

Arkansas Children's Hospital Research Institute and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (J.C.R., R.H., M.J.J.R., T.M.B.); and Department of Biochemistry and Molecular Biology, The University of Texas Medical School, Houston, Texas (H.W., H.W.S.)

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 6beta -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 6beta -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-Km chlorzoxazone hydroxylase.

1 This study was supported in part by funding from the National Institute of Alcohol and Alcoholism Grant AA08645 and the National Institute of Mental Health Grant MH58297.

2 This research was presented in part at the Society of Toxicology meeting, New Orleans, LA, 1999.

0022-3565/00/2952-0747$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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