An investigation of the mechanism of hepatotoxicity of the antitumour agent N-methylformamide in mice.

N-Methylformamide (NMF) has been reported to cause liver damage in animals and man. This hepatotoxicity was characterized in BALB/c mice by the release of liver enzymes into the plasma and by histopathological examination of livers after single and repeated administration of NMF. Whereas plasma levels of sorbitol dehydrogenase were elevated dramatically 24 hr after 400 mg/kg given as a single dose, the glutathione content of the livers was not different from controls even after repeated administration. Liver damage was apparent on gross inspection and was defined as periacinar necrosis on histopathology. A dose of 100 mg/kg did not cause damage even after repeated injections on five consecutive days. The hypothesis that NMF is metabolized to a chemically reactive species was tested. Incubation of mouse hepatocytes with 7 mM NMF for 80 min produced a decrease in intracellular glutathione. Exposure of hepatocytes to NMF for 240 min led to the production of breakdown products of lipid peroxides at levels significantly above controls. However, incubation of microsomes or mitochondria with NMF and NADPH did not lead to raised levels of lipid peroxides. The effects described were specific to NMF as incubation of N,N-dimethylformamide, N-hydroxymethylformamide or formamide with hepatocytes did not result in glutathione depletion or increased lipid peroxidation. NMF undergoes extensive metabolism in vivo and the results indicate that NMF forms a chemically reactive metabolite, even though incubation of the drug with liver fractions or hepatocytes did not lead to metabolites at levels which were analytically identifiable.