Covalent binding of niridazole (Ambilhar) to tissue proteins of the rat

In vivo and in vitro experiments have shown that [14C] niridazole ( NDZ ) can covalently bind to the proteins of rat liver, kidney and testes, but not to the DNA in these tissues. The covalent binding was dose dependent, and the greatest amount of binding was found in the microsomal fraction. The binding of [14C] NDZ to microsomal protein was linear with time and with protein concentration. Reduced nicotinamide adenine dinucleotide phosphate was necessary for the binding, while cobaltous chloride pretreatment inhibited it, demonstrating that a cytochrome P-450 dependent mixed function oxidase mediated the binding. Pretreatment of rats with other compounds, such as phenobarbital, 3-methyl-cholanthrene and chloracetamide which alter the rate of metabolism of [14C] NDZ similarly affected the extent of hepatic binding of the radiolabelled metabolite. The possible relationships between these results and the cytotoxic effects of NDZ have been discussed.