Hepatotoxicity of N-methylformamide in mice--I. 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.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D005559:Formamides / Q000633:toxicity*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism*; D019803:Glutathione Disulfide; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA
D005559:Formamides; D007064:L-Iditol 2-Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D019803:Glutathione Disulfide; C002950:methylformamide