Van den Bulcke M, Rosseel M T, Wijnants P, Buylaert W, Belpaire F M
Heymans Institute of Pharmacology, University of Ghent Medical School, Belgium.
Arch Toxicol. 1994;68(5):291-5. doi: 10.1007/s002040050071.
The metabolism and hepatotoxicity of N,N-dimethylformamide (DMF) and two of its metabolites, N-hydroxymethyl-N-methylformamide (HMMF) and N-methylformamide (NMF) were evaluated over a 4-day period in rats. DMF toxicity was dose dependent and delayed toxicity after the administration of a high DMF dose (13.7 mmol/kg) in comparison to a lower dose (4.1 mmol/kg) was observed. Treatment of rats with 13.7 mmol/kg DMF, HMMF, or NMF showed i) that DMF is more toxic than HMMF or NMF, and ii) that hepatotoxicity occurs later for DMF than for HMMF or NMF. Analysis of serum and urine samples demonstrated that DMF is first metabolized to HMMF, which is then partially converted to NMF. After HMMF administration, NMF was found both in serum and in urine. The time course of DMF and HMMF toxicity in relation to NMF formation fitted the hypothesis that the hepatotoxicity of DMF and HMMF is mediated via NMF. The degree of hepatotoxicity after HMMF and NMF treatment is similar. However, the degree of DMF hepatotoxicity is much higher than in the case of NMF or HMMF. The role of NMF as an obligatory intermediate in DMF and HMMF hepatotoxicity is discussed.
在4天的时间里，对大鼠体内N，N - 二甲基甲酰胺（DMF）及其两种代谢产物N - 羟甲基 - N - 甲基甲酰胺（HMMF）和N - 甲基甲酰胺（NMF）的代谢及肝毒性进行了评估。DMF的毒性呈剂量依赖性，与较低剂量（4.1 mmol/kg）相比，给予高剂量DMF（13.7 mmol/kg）后观察到延迟毒性。用13.7 mmol/kg DMF、HMMF或NMF处理大鼠表明：i）DMF比HMMF或NMF毒性更强；ii）DMF引起肝毒性的时间比HMMF或NMF更晚。血清和尿液样本分析表明，DMF首先代谢为HMMF，然后HMMF部分转化为NMF。给予HMMF后，在血清和尿液中均发现了NMF。DMF和HMMF毒性与NMF形成的时间进程符合以下假设：DMF和HMMF的肝毒性是通过NMF介导的。HMMF和NMF处理后的肝毒性程度相似。然而，DMF的肝毒性程度远高于NMF或HMMF。文中讨论了NMF作为DMF和HMMF肝毒性中必需中间体的作用。
