Protection against carbon tetrachloride hepatotoxicity by pretreatment with indole-3-carbinol.
The effects of administering indole-3-carbinol (I-3-C) on carbon tetrachloride (CCl4)-induced hepatotoxicity were examined. Mice received by gavage 0-150 mg I-3-C/kg body wt in methanol-extracted corn oil, followed 1 h later by 15 microliters CCl4/kg body wt in corn oil. Animals were sacrificed 24 h after receiving CCl4. Pretreatment with I-3-C reduced the degree of centrolobular necrosis, as observed histologically. Additionally, CCl4-mediated elevated serum enzymes were reduced by I-3-C. Although I-3-C induced elevated levels of cytochrome P-450 and associated mixed-function oxidase activity, the CCl4 depression of these parameters was not clearly reversed by I-3-C. However, CCl4 produced decreases in hepatic levels of glutathione (GSH), total reducing equivalents, and protein sulfhydryls, all of which were restored to control levels by I-3-C. Using mouse liver microsomes in an NADPH-fortified reaction mixture, I-3-C inhibited, in a concentration-dependent manner, CCl4-initiated lipid peroxidation, with 50% inhibition at 35-40 microM I-3-C. When mice were treated by gavage with 50 mg [14C]I-3-C/kg body wt, concentrations of radiolabel in the liver were greater than 100 microM after 1 hr. This was five times the level of radioactivity measured in blood and three times the concentration of I-3-C necessary for 50% inhibition of CCl4-mediated lipid peroxidation in vitro. The data are consistent with the hypothesis that I-3-C intervenes in CCl4-mediated hepatic necrosis by combining with reactive free radical metabolites of CCl4, thereby protecting critical cellular target sites.
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D002251:Carbon Tetrachloride / Q000037:antagonists & inhibitors; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy* / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009954:Ornithine Carbamoyltransferase / Q000097:blood; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000378:metabolism
D007211:Indoles; D008054:Lipid Peroxides; D013438:Sulfhydryl Compounds; D003577:Cytochrome P-450 Enzyme System; C016517:indole-3-carbinol; D002251:Carbon Tetrachloride; D006899:Mixed Function Oxygenases; D009954:Ornithine Carbamoyltransferase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase