Alcohol-mediated effects on the level of cytochrome P-450 and heme biosynthesis in cultured rat hepatocytes.
Interaction of alcohol and drugs in the liver appears to involve common microsomal oxidative enzymes which utilize cytochrome P-450. Since alcohol augments the toxicity of a variety of drugs, the regulation of the P-450 hemoprotein, a primary component in hepatic drug metabolizing systems, may play a vital role in this phenomenon. We utilize an adult rat liver culture system as a model to explore the action of levels of alcohol below that which is necessary to produce intoxication in humans. The addition of 16 mM ethanol (70 mg/dl) to these hepatocytes results in a 49.5% decrease in cytochrome P-450 activity after 24 h, and a 3-fold increase in the activity of delta-aminolevulinate synthase, the rate-limiting enzyme in hepatic heme biosynthesis. Furthermore, ethanol treatment also causes a transient decrease in the level of intracellular heme. However, the diminished level of total heme does not appear to act as a repressor for delta-aminolevulinate synthase, since it occurs after the initial stimulation of the enzyme by ethanol.
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D006418:Heme / Q000096:biosynthesis*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000431:Ethanol; D006418:Heme; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System; D000624:5-Aminolevulinate Synthetase