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Hepatotoxicity of N-methylformamide in mice--I. Relationship to glutathione status
Abstract:
In order to investigate the link between hepatotoxicity caused by N-methylformamide (NMF) and its ability to deplete hepatic glutathione experiments were conducted in three strains of mouse which differ in their susceptibility towards NMF-induced liver damage. NMF toxicity was measured by changes in plasma levels of sorbitol dehydrogenase and alanine and aspartate transaminases. In BALB/c mice, the most susceptible strain, a hepatotoxic dose of NMF (200 mg/kg) caused a depletion of hepatic glutathione to 21% of control levels 2 hr after drug administration. In CBA/CA and BDF1 mice the same dose of NMF depleted glutathione to 53% of control levels and did not cause hepatotoxicity. In BALB/c mice depletion of hepatic glutathione by pretreatment with buthionine sulfoximine decreased the hepatotoxic dose threshold of NMF from 150 mg/kg to 100 mg/kg. Conversely, pretreatment of mice with cysteine or N-acetylcysteine protected against both glutathione depletion and NMF-induced hepatotoxicity. The results are in accordance with the suggestion that the hepatotoxicity of NMF is associated with its metabolism to an intermediate which reacts with glutathione.
Insights
N-methylformamide (NMF) causes liver damage by depleting hepatic glutathione. Protecting glutathione levels in mice prevented NMF-induced hepatotoxicity, confirming this link.
Area of Science:
- Toxicology
- Biochemistry
- Pharmacology
Background:
- Hepatotoxicity is a significant concern with certain chemical exposures.
- Hepatic glutathione plays a crucial role in cellular defense mechanisms against toxins.
Purpose of the Study:
- To investigate the relationship between N-methylformamide (NMF)-induced hepatotoxicity and hepatic glutathione depletion.
- To explore the protective effects of glutathione modulation on NMF toxicity.
Main Methods:
- Experiments were conducted in three mouse strains with varying susceptibility to NMF.
- Hepatotoxicity was assessed by measuring plasma enzyme levels (sorbitol dehydrogenase, ALT, AST).
- Hepatic glutathione levels were quantified following NMF administration and in response to pre-treatments.
Main Results:
- Susceptible BALB/c mice showed significant hepatic glutathione depletion (to 21% of control) and hepatotoxicity after NMF exposure.
- Less susceptible CBA/CA and BDF1 mice exhibited less glutathione depletion (53% of control) and no significant liver damage.
- Depleting glutathione with buthionine sulfoximine lowered the NMF hepatotoxic dose threshold, while cysteine or N-acetylcysteine pre-treatment offered protection.
Conclusions:
- NMF-induced hepatotoxicity is strongly associated with the depletion of hepatic glutathione.
- Metabolism of NMF to an intermediate that reacts with glutathione is implicated in its toxic mechanism.
- Modulating glutathione levels offers a potential strategy to mitigate NMF-induced liver injury.