METABOLISM AND HEPATOTOXICITY OF N,N-DIMETHYLFORMAMIDE, N-HYDROXYMETHYL-N-METHYLFORMAMIDE, AND N-METHYLFORMAMIDE IN THE RAT

The metabolism and hepatotoxicity of N,N-dimethylformamide (DMF) and t wo 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 administrat ion 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, HMM F, or NMF showed i) that DMF is more toxic than HMMF or NMF, and ii) t hat 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 administr ation, NMF was found both in serum and in urine. The time course of DM F and HMMF toxicity in relation to NMF formation fitted the hypothesis that the hepatotoxicity of DMF and HMMF is mediated via NMF The degre e of hepatotoxicity after HMMF and NMF treatment is similar. However, the degree of DMF hepatotoxicity is much higher than in the case of NM F or HMMF The role of NMF as an obligatory intermediate in DMF and HMM F hepatotoxicity is discussed.