Abstract
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. TheCYP3A2 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 ofCYP3A 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-Km chlorzoxazone hydroxylase.
Footnotes
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Send reprint requests to: Dr. J. Craig Rowlands, University Arkansas for Medical Sciences, 1120 S. Marshall St., S-512-20B, Little Rock, AR 72202. E-mail:rowlandscraig{at}exchange.uams.edu
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↵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.
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↵2 This research was presented in part at the Society of Toxicology meeting, New Orleans, LA, 1999.
- Abbreviations:
- CYP
- cytochrome P450
- CHO
- carbohydrate
- GH
- growth hormone
- Received December 15, 1999.
- Accepted July 20, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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