Comparative hepatotoxicity and metabolism of N-methylformamide in rats and mice.
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.
Tulip
K
K
Department of Pharmacology, School of Pharmacy, University of London, UK.
Timbrell
J A
JA
D000818:Animals; D019328:Buthionine Sulfoximine; D002250:Carbon Radioisotopes; D005559:Formamides / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000032:analysis; D008099:Liver / Q000187:drug effects*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013438:Sulfhydryl Compounds / Q000032:analysis
D002250:Carbon Radioisotopes; D005559:Formamides; D008298:Maleates; D013438:Sulfhydryl Compounds; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C014476:diethyl maleate; D005978:Glutathione; C002950:methylformamide