Comparative hepatotoxicity and metabolism of N-methylformamide in rats and mice

Arch Toxicol. 1988;62(2-3):167-76. doi: 10.1007/BF00570135.

Abstract

N-methylformamide (NMF) produced dose-dependent zone 3 haemorrhagic necrosis in mice; the threshold dose was 100-200 mg/kg. In rats a dose of 1000 mg/kg caused hepatic damage in some animals and slight elevations of plasma transaminases. A species difference in susceptibility to NMF-induced hepatotoxicity is clearly indicated. NMF depleted liver non-protein sulphydryl (NPSH) in a dose-dependent manner in mice, but not in rats. Depletion of liver glutathione by buthionine sulphoximine or diethylmaleate potentiated the hepatotoxicity of NMF in mice. [14C]-methyl NMF was metabolised by mice and rats and a number of urinary metabolites including an N-acetylcysteine conjugate, methylamine and N-hydroxymethylformamide were detected. There were no qualitative differences in the metabolites between rats and mice but mice metabolised NMF much faster and more extensively than rats.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Buthionine Sulfoximine
  • Carbon Radioisotopes
  • Formamides / metabolism
  • Formamides / toxicity*
  • Glutathione / analysis
  • Liver / drug effects*
  • Male
  • Maleates / pharmacology
  • Methionine Sulfoximine / analogs & derivatives
  • Methionine Sulfoximine / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Rats
  • Rats, Inbred Strains
  • Species Specificity
  • Sulfhydryl Compounds / analysis

Substances

  • Carbon Radioisotopes
  • Formamides
  • Maleates
  • Sulfhydryl Compounds
  • Methionine Sulfoximine
  • Buthionine Sulfoximine
  • diethyl maleate
  • Glutathione
  • methylformamide