An investigation of the relationship between hepatotoxicity and the metabolism of Nalkyl-formamide

The hepatotoxicity and metabolism of the following close analogs of the hepatotoxc antitumor agent N-methylformamide (NMF) were investigated in CBA/CA mice: N-ethylformamide (NEF), dimethylformamide (DMF), formamide and N-methyincetamide (NMA). Apart from NMF only NEF waspotently hepatotoxic as measured by the elevation of plasma activities of the enzymes sorbitol dehydrogenase and alanine and aspartate aminofrans-ferases 24 hr after drug administration. In freeze-dried urine samples of mice whh had receved NEF or NMF, but not inthe case of DMF, formamide or NMA, thioesters were detected by thin-layer chromatography. Evidence based on high-pressure liquid chromatography analysis and 400 MHz 1H-NMR and mass spectrometry SUggeStS that the thioester metabolite of NEF is S-(N-ethylcarbamoyl)-N-acetylcystelne. It has been shown pre-viously that NMF is metabolized to S-(N-methylcarbamoyl)-N