HEPATOTOXICITY OF N-METHYLFORMAMIDE IN MICE .1. RELATIONSHIP TO GLUTATHIONE STATUS

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.