PT  - JOURNAL ARTICLE
AU  - M D Threadgill
AU  - D B Axworthy
AU  - T A Baillie
AU  - P B Farmer
AU  - K C Farrow
AU  - A Gescher
AU  - P Kestell
AU  - P G Pearson
AU  - A J Shaw
TI  - Metabolism of N-methylformamide in mice: primary kinetic deuterium isotope effect and identification of S-(N-methylcarbamoyl)glutathione as a metabolite.
DP  - 1987 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 312--319
VI  - 242
IP  - 1
4099  - http://jpet.aspetjournals.org/content/242/1/312.short
4100  - http://jpet.aspetjournals.org/content/242/1/312.full
SO  - J Pharmacol Exp Ther1987 Jul 01; 242
AB  - S-(N-Methylcarbamoyl)glutathione has been identified by cesium ion liquid secondary ion mass spectrometry as a biliary metabolite in mice of the experimental antitumor agent and hepatotoxin N-methylformamide. Metabolism of N-methylformamide to urinary methylamine, urinary N-acetyl-S-(N-methylcarbamoyl)-cysteine and biliary S-(N-methylcarbamoyl)glutathione was found to be subject to large intermolecular primary kinetic isotope effects when hydrogen was replaced by deuterium in the formyl group (kH/kD = 5.5 +/- 0.2, 4.5 +/- 1.0 and 7 +/- 2, respectively), as shown by mass spectrometry of derivatives of these metabolites. These values indicate the existence of a common metabolic precursor for each of these metabolites. In particular, methylamine is shown not to arise from simple enzymatic hydrolysis of N-methylformamide but is associated with an oxidative process. Therefore, it is highly likely that N-methylformamide is oxidized and conjugated to form S-(N-methylcarbamoyl)glutathione which is metabolized further to N-acetyl-S-(N-methylcarbamoyl) cysteine. Either of these thiocarbamates could be hydrolyzed to give the parent thiol and the observed metabolic end products, methylamine and carbon dioxide. The presence of deuterium in the formyl moiety of N-methylformamide reduced markedly the hepatotoxicity of the compound, as shown by measurements of the activities of appropriate hepatic enzymes in plasma.