Hepatotoxicity of vitamin A and ethanol in the rat.
To study the possible hepatotoxicity of vitamin A supplementation and its potentiation by ethanol, rats were fed diets with either normal or fivefold increased vitamin A content, both with or without ethanol. Ethanol with a normal vitamin A diet produced the expected proliferation of the smooth endoplasmic reticulum and moderate mitochondrial lesions. Vitamin A supplementation by itself produced endoplasmic reticulum proliferation, slight enlargement of mitochondria, and moderate decrease in cytochrome oxidase activity and cytochrome aa3 content. The combination of high vitamin A and ethanol resulted in much more striking lesions, with giant mitochondria containing paracrystalline inclusions and depression of oxygen consumption in state-3 respiration with five different substrates, including palmitate and palmitoyl coA. The depression of fatty acid oxidation may have contributed to the lipid accumulation. The blood levels of vitamin A were unaffected whereas liver levels of vitamin A were increased by vitamin A supplementation and decreased by ethanol. As a net result the liver vitamin A content of the high-A-ethanol groups was not greater than that of the normal-A-control group, suggesting that a metabolite of vitamin A rather than vitamin A itself may have been responsible for the potentiation of vitamin A toxicity by ethanol. Mitochondrial toxicity reflected itself also in decreased content of various cytochromes and reduced activity of enzymes, including glutamate dehydrogenase. The activity of the latter was increased in the serum. Implications of these findings for the routine treatment of alcoholics with vitamin A and the monitoring for possible signs of toxicity are discussed.
D000818:Animals; D004357:Drug Synergism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012177:Retinol-Binding Proteins / Q000378:metabolism; D014801:Vitamin A / Q000633:toxicity*
D012177:Retinol-Binding Proteins; D014801:Vitamin A; D000431:Ethanol; D005969:Glutamate Dehydrogenase; D003576:Electron Transport Complex IV