Mode of action

A short-lived intermediate metabolite, possibly methyl isocyanate or its conjugate, SMG, is thought to be responsible for the hepatotoxicity of DMF (Gescher, 1993).

Hepatotoxicity is observed later when a high dose of DMF is given compared to the onset when a low dose is administered (Lundberg et al., 1981; Van den Bulcke et al., 1994). DMF has been shown to inhibit its own metabolism (Mraz et al., 1993). It is a competitive inhibitor of the generation of the toxic metabolite and thus SMG from NMF (Gescher, 1993). This accounts for the long-half life of AMCC and the delay in the onset of toxicity (Gescher, 1993).

When several formamide analogues were administered to mice only those forming mercapturic acids caused hepatotoxicity (Kestell et al., 1987).

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