Related Experiment Videos
Protection from N-nitrosodimethylamine-mediated liver damage by indole-3-carbinol
H G Shertzer1, M W Tabor, M L Berger
1Department of Environmental Health, University of Cincinnati Medical Center, Ohio 45267-0056.
Abstract:
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.
Insights
Indole-3-carbinol (I-3-C) protects mice from liver damage caused by N-nitrosodimethylamine (NDMA). I-3-C reduces necrosis and liver enzyme release, but not by inhibiting NDMA metabolism.
Area of Science:
- Toxicology
- Hepatoprotective Agents
- Dietary Compounds
Background:
- N-nitrosodimethylamine (NDMA) is a potent hepatotoxin causing significant liver damage.
- Indole-3-carbinol (I-3-C) is a compound found in cruciferous vegetables with potential health benefits.
Purpose of the Study:
- To investigate the protective effects of Indole-3-carbinol (I-3-C) against N-nitrosodimethylamine (NDMA)-induced hepatotoxicity in mice.
- To elucidate the mechanisms underlying I-3-C's protective action against liver injury.
Main Methods:
- Mice were treated with I-3-C prior to NDMA administration.
- Hepatotoxicity was assessed by histopathological examination and measurement of plasma liver enzymes.
- Cytochrome P-450 activity and ascorbate levels were also evaluated.
Main Results:
- I-3-C significantly reduced NDMA-induced hemorrhagic and necrotic liver lesions.
- I-3-C administration lowered plasma alanine transaminase and ornithine transcarbamylase levels.
- I-3-C prevented the decline in tissue ascorbate levels but did not inhibit NDMA-induced decreases in cytochrome P-450 or NDMA demethylase activity.
Conclusions:
- Indole-3-carbinol (I-3-C) demonstrates significant hepatoprotective effects against NDMA-induced liver injury in mice.
- The protective mechanism of I-3-C is independent of its direct inhibition of NDMA metabolic activation.
- I-3-C's ability to preserve ascorbate levels may contribute to its protective effects.