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Modulation of monocrotaline-induced hepatic genotoxicity in rats
Abstract:
Monocrotaline (MCT), a hepatotoxic/hepatocarcinogenic pyrrolizidine alkaloid (PA) induced DNA-DNA interstrand crosslinks in a dose-dependent manner through 30 mg/kg. Hepatic cytochrome P-450 has been shown to bioactivate MCT to pyrrole derivatives which are thought to be responsible for these genotoxic lesions. We have hypothesized these lesions to be related to the adverse hepatic actions of MCT and other PAs. Studies reported here investigated the effect of phenobarbital, a P-450 inducer, 2-dimethylaminoethyl-2,2-diphenylvalerate, a P-450 inhibitor and butylated hydroxyanisole, a dietary antioxidant, on hepatic DNA-DNA interstrand cross-links induced by a single dose of MCT (15 mg/kg i.p.) administered to male Sprague-Dawley rats. DNA damage was assessed by alkaline elution. The effects of these pretreatment regimens on MCT-induced DNA-DNA interstrand cross-linking was qualitatively similar to their reported effects on the hepatotoxicity of MCT. The effects of these pretreatments on hepatic cytochrome P-450 content, hepatic non-protein sulfhydryl levels and hepatic glutathione S-transferase activities were similarly investigated in attempts to explain the observed effects on DNA cross-link induction. These data provide further support for the association between DNA damage and the adverse hepatic effects of MCT.
Insights
Monocrotaline causes DNA damage in the liver. Pre-treatments affecting liver enzymes altered this DNA damage, suggesting a link between genotoxicity and liver injury from pyrrolizidine alkaloids.
Area of Science:
- Hepatotoxicity
- Genotoxicity
- Pharmacology
Background:
- Monocrotaline (MCT), a pyrrolizidine alkaloid (PA), is hepatotoxic and hepatocarcinogenic.
- MCT induces DNA-DNA interstrand crosslinks dose-dependently.
- Hepatic cytochrome P-450 bioactivates MCT to genotoxic pyrrole derivatives.
Purpose of the Study:
- Investigate the effects of P-450 modulators on MCT-induced DNA damage.
- Explore the relationship between DNA cross-linking and MCT hepatotoxicity.
- Examine the impact of pretreatments on hepatic P-450 content, sulfhydryl levels, and glutathione S-transferase activity.
Main Methods:
- Male Sprague-Dawley rats were pretreated with phenobarbital (P-450 inducer), P-450 inhibitor, or antioxidant.
- A single dose of MCT (15 mg/kg) was administered.
- DNA damage was quantified using alkaline elution.
- Hepatic P-450 content, non-protein sulfhydryl levels, and glutathione S-transferase activities were measured.
Main Results:
- Pretreatment effects on DNA-DNA interstrand cross-linking were qualitatively similar to their effects on MCT hepatotoxicity.
- Phenobarbital, P-450 inhibitor, and antioxidant modulated MCT-induced DNA cross-linking.
- Changes in hepatic P-450, sulfhydryl, and glutathione S-transferase levels correlated with DNA damage modulation.
Conclusions:
- The study supports an association between MCT-induced DNA damage and adverse hepatic effects.
- Modulation of hepatic P-450 pathways influences MCT genotoxicity.
- These findings contribute to understanding the mechanisms of PA-induced liver injury.