Comparison of N-Methylformamide-Induced Hepatotoxicity and Metabolism in Rats and Mice

  • K. Tulip
  • J. K. Nicholson
  • J. A. Timbrell
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 197)


N-Methylformamide (NMF) is a solvent and a potential anticancer drug which is hepatotoxic in man (1); mice (2) and rats (3) causing centrilobular hepatic necrosis. However, the mechanism underlying this hepatotoxicity is currently unknown. NMF is extensively metabolised in mice in vivo (4)(Fig. 1). However, no metabolism has been detected in vitro in liver fractions or isolated hepatocytes (2). N-hydroxymethyl formamide (NMFOH) has been indirectly identified as a urinary metabolite of NMF (4). NMF causes depletion of non-protein thiols in vivo in mice (5) and in mouse hepatocytes (2) and also causes lipid peroxidation in hepatocytes (2). Although NMF has been reported to be hepatotoxic in rats (3) as well as mice, in our hands, rats were very much less sensitive. Consequently we have investigated the metabolism and toxicity of NMF in both rats and mice, to determination the possible correlation between metabolism and toxicity.


Covalent Binding Urinary Metabolite Aspartate Transaminase Radioactive Metabolite NADPH Generate System 
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  1. 1.
    W.P.L. Myers, D. Karnofsky and J.H. Burchenal. The hepatotoxic action of N-methylformamide in man. Cancer, 9: (1956).Google Scholar
  2. 2.
    H. Whitby, A Gescher and L. Levy. An investigation of the mechanism of hepatotoxicity of the antitumour agent N-methylformamide in mice. Biochem. Pharmacol. 33: 295 (1984).PubMedCrossRefGoogle Scholar
  3. 3.
    I. Lundberg, S. Lundberg and T. Kronevi. Some observations on dimethylformamide hepatotoxicity. Toxicology 22: 1 (1981).PubMedCrossRefGoogle Scholar
  4. 4.
    C. Brindley, A. Gescher, E.S. Harpur, D. Ross, J.A. Slack, M.D. Threadgill and H. Whitby. Studies on the pharmacology of N-methylformamide in mice. Cancer Treatments Reports 66: 1957 (1982).Google Scholar
  5. 5.
    A. Gescher, N.W. Gibson, J.A. Hickman, S.T. Langdon, D. Ross and G. Atassi. N-Methylformamide: Antitumour activity and metabolism in mice. Brit. J. Cancer 45: 843 (1982).PubMedCrossRefGoogle Scholar
  6. 6.
    H. Jeffay and J.Alvarez. Liquid scintillation counting of carbon carbon-14. Anal. Chem. 33: 612 (1961).CrossRefGoogle Scholar
  7. 7.
    M.D. Threadgill and E.N. Gate. Labelled compounds of interest as antitumour agents I: N-Methylformamide and N,N-dimethylformamide. J. Lab. IId Cmpds. Radiopharm. XX: 447 (1983).Google Scholar
  8. 8.
    G.L. Ellman. Tissue sulphydryl groups. Arch. Biochem. Biophys. 82: 70 (1955).CrossRefGoogle Scholar
  9. 9.
    R.A. Prough and D.M. Zeigler. The relative participation of liver microsomal amine oxidase and cytochrome P450 in N-demethylation reactions. Arch. Biochem. Biophys. 180: 363 (1977).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • K. Tulip
    • 1
  • J. K. Nicholson
    • 1
  • J. A. Timbrell
    • 1
  1. 1.Toxicology Unit, Department of Pharmacology The School of PharmacyUniversity of LondonLondonUK

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