Metabolism of N-methylformamide in mice: primary kinetic deuterium isotope effect and identification of S-(N-methylcarbamoyl)glutathione as a metabolite.
Metabolism of N-methylformamide in mice: primary kinetic deuterium isotope effect and identification of S-(N-methylcarbamoyl)glutathione as a metabolite.
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发表时间：
1987-07
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通讯作者：
M. Threadgill;D. Axworthy;T. Baillie;P. Farmer;K. Farrow;A. Gescher;P. Kestell;P. Pearson;A. J. Shaw
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作者：
M. Threadgill;D. Axworthy;T. Baillie;P. Farmer;K. Farrow;A. Gescher;P. Kestell;P. Pearson;A. J. Shaw
用铯离子液体二次离子质谱法鉴定了S-（N-甲基氨基甲酰基）谷胱甘肽为实验性抗肿瘤药物和肝毒素N-甲基甲酰胺在小鼠胆汁中的代谢产物。N-甲基甲酰胺代谢为尿甲胺、尿N-乙酰基-S-（N-甲基氨基甲酰基）-半胱氨酸和胆汁S-当甲酰基中的氢被氘取代时，（N-甲基氨基甲酰基）谷胱甘肽受到大的分子间初级动力学同位素效应的影响（kH/kD分别为5.5 +/- 0.2、4.5 +/- 1.0和7 +/- 2），如这些代谢物衍生物的质谱所示。这些值表明这些代谢物中的每一种存在共同的代谢前体。特别是，甲胺不产生于简单的酶水解N-甲基甲酰胺，但与氧化过程。因此，N-甲基甲酰胺极有可能被氧化并结合形成S-（N-甲基氨基甲酰基）谷胱甘肽，其进一步代谢为N-乙酰基-S-（N-甲基氨基甲酰基）半胱氨酸。这两种硫代氨基甲酸酯均可水解，得到母体硫醇和观察到的代谢终产物甲胺和二氧化碳。在N-甲基甲酰胺的甲酰基部分的氘的存在下，显着降低该化合物的肝毒性，如通过测量血浆中适当的肝酶的活性所示。
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.