Hepatotoxicity and P-4502E1-dependent metabolic oxidation of N,N-dimethylformamide in rats and mice

 A comparative biochemical and histological study on the hepatotoxicity of a single dose of N,N-dimethylformamide (DMF) and N-methylformamide (NMF) in control and acetone-treated SD male rats and CD-1 male mice was performed. In control and acetone-pretreated rats, neither DMF nor NMF caused hepatic damage or elevation of plasma transaminases. In contrast, in acetonized but not in control mice, DMF administration yielded some evidence of liver necrosis and elevation of ALAT (alanine-amino transferase) activity. After a DMF dose of 1000 mg/kg, ALAT activity was found 1215± 832 mU/ml and 47±18 mU/ml in acetonized and control mice, respectively. NMF treatment was hepatotoxic in control mice and lethal in acetonized mice. In control mice, an NMF dose of 600 mg/kg increased ALAT activity from a basal value of 35±5 to 2210± 1898 mU/ml. When the oxidative metabolism of DMF was investigated, microsomes from both rats and mice preinduced by acetone increased the demethylation rate of DMF 7 to 10-fold compared to that (about 0.25 nmol/min per mg protein) of the corresponding control microsomes. The enzymatic affinities for DMF oxidation, however, were different: in mice the K_m (0.05 mM) was one order of magnitude lower than that (0.56 mM) found in rats. The experiments performed with purified rat and mouse P-450 2E1 in a reconstituted system confirmed that the P-450 2E1 isoforms are very active catalysts towards DMF oxidation (the turnover was about 10 nmol/min per nmol P-450 for both enzymes) but with a strikingly different affinity. Whereas the K_m for mouse P-450 2E1 was 0.08± 0.03 mM, that for rat P-450 2E1 was 1.1±0.2 mM. These findings indicate that the higher susceptibility of mice, compared with rats, to DMF hepatotoxicity, could be ascribed, at least in part, to the higher metabolic capacity of mouse P-450 2E1 with respect to that of rats. Received: 6 July 1994 / Accepted: 20 September 1994