Protection from N-nitrosodimethylamine-mediated liver damage by indole-3-carbinol.
Indole-3-carbinol (I-3-C) was examined for its ability to protect mice against 24-hr N-nitrosodimethylamine (NDMA)-mediated hepatotoxicity. NDMA (20 mg/kg body weight) alone produced extensive hemorrhagic and centrolobular necrotic lesions, with a necrotic severity index of 3.0 +/- 0.4 (scale of 0-5). Treatment with 50 mg/kg body weight of I-3-C by gavage, 1 hr prior to NDMA, substantially protected against hemorrhagic lesions. Furthermore, I-3-C lowered the NDMA-mediated tissue necrotic index to 1.5 +/- 0.3, by reducing the extent of tissue necrosis rather than the severity in the necrotic region. Release of liver enzymes into the blood correlated with the histopathology; I-3-C reduced NDMA-mediated elevated activities of plasma alanine transaminase and ornithine transcarbamylase by 84 and 51.3%, respectively. Although no changes in nonprotein sulfhydryls were evident at 24-hr after NDMA, ascorbate levels were reduced to 40% of control values. However, treatment with I-3-C prior to NDMA prevented the decline in tissue ascorbate concentrations. In vitro, I-3-C was found to be a type II ligand for cytochrome P-450, with a Ks value of 237 microM. However, if such binding occurs in vivo, it does not protect against the approximately 60% decrease in hepatic cytochrome P-450 or the 80% decrease in NDMA demethylase I activity produced by NDMA. Since I-3-C slightly enhances cytochrome P-450 content and NDMA demethylase activity, the histopathologic protection by I-3-C must be due to factors other than inhibiting metabolic activation of NDMA.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008107:Liver Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism; D009336:Necrosis / Q000517:prevention & control; D009954:Ornithine Carbamoyltransferase / Q000097:blood; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism
D007211:Indoles; D003577:Cytochrome P-450 Enzyme System; C016517:indole-3-carbinol; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D009954:Ornithine Carbamoyltransferase; D000410:Alanine Transaminase; D004128:Dimethylnitrosamine