Vitamin A potentiation of carbon tetrachloride hepatotoxicity: enhanced lipid peroxidation without enhanced biotransformation.
To better understand the mechanism by which vitamin A (VA, retinol) potentiates the hepatotoxicity of carbon tetrachloride, its effect on metabolism and covalent binding of CCl4 as well as its effect on lipid peroxidation was determined. 14CCl4 (0.15 ml/kg, 21.4 microCi/mmol) was administered to male SD rats that had been treated with vitamin A (250,000 IU/kg/day for 1 week) or vehicle. Vitamin A pretreatment did not increase the 24-hr biotransformation of 14CCl4 to 14CO2, to exhaled volatile organics, or to metabolites excreted in the urine or feces. Furthermore, there was no dramatic effect of vitamin A pretreatment on the covalent binding of 14CCl4 equivalents to hepatic lipids and proteins at early time points (1/2-4 hr) after administration of 14CCl4. The microsomal concentration of cytochrome P450 was unchanged by vitamin A treatment. There was a dramatic increase (6-8x) in the amount of ethane exhaled in those rats treated with vitamin A and then administered CCl4 compared to that of those administered CCl4 without pretreatment. The enhanced lipid peroxidation as evidenced by the increased exhalation of ethane was not the result of vitamin A-induced decreases in hepatic glutathione or vitamin E. These data indicate that the potentiation of CCl4 hepatotoxicity by vitamin A pretreatment is associated with an enhancement of lipid peroxidation that is independent of changes in CCl4 biotransformation or the hepatic concentration of two important hepatoprotective agents.
elSisi
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AE
Department of Pharmacology, University of Arizona, Tucson 85721.
Earnest
D L
DL
Sipes
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D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002250:Carbon Radioisotopes; D002251:Carbon Tetrachloride / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004357:Drug Synergism; D050356:Lipid Metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014801:Vitamin A / Q000494:pharmacology*; D014810:Vitamin E / Q000378:metabolism
D002250:Carbon Radioisotopes; D011506:Proteins; D013438:Sulfhydryl Compounds; D014801:Vitamin A; D014810:Vitamin E; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride