Investigation of the mechanism of hepatotoxicity of N-methylformamide in mice: effects on calcium sequestration in hepatic microsomes and mitochondria and on hepatic plasma membrane potential
Whitby, H.; Chahwala, S.B.; Gescher, A.
Biochemical and Biophysical Research Communications 125(2): 712-718
N-Methylformamide is an antitumour drug with hepatotoxic properties. Three potential targets for hepatocellular toxic lesions caused by N-methylformamide were investigated: the mitochondrial and microsomal Ca2+ pumps and the functional integrity of the plasma membrane. The administration of N-methylformamide to mice caused a dramatic decrease in the ability of the liver mitochondria to sequester [45Ca2+]. This effect was dose-dependent and was not caused by dimethylformamide, N-hydroxymethylformamide or formamide. The microsomal Ca2+ pump was not affected by N-methylformamide. Incubations of isolated mitochondria with N-methylformamide for 1 hr also led to the inhibition of the Ca2+ sequestration. Incubation of isolated mouse hepatocytes with N-methylformamide did not cause changes in plasma membrane potential as measured using the lipophilic cation triphenylmethylphosphonium. Of the three targets studied, the mitochondrial Ca2+ pump may be the one through which N-methylformamide triggers the events leading ultimately to hepatic necrosis.