The mechanism of anticoccidial action of arprinocid-1-N-oxide.

Neither arprinocid nor its liver microsomal metabolite arprinocid-1-N-oxide binds to calf thymus DNA. Neither compound showed an effect on the synthesis of DNA, RNA, or proteins in HeLa cells or on the rate of respiration by Eimeria tenella mitochondria. The 1-N-oxide differs from the parent compound by its toxic effect on HeLa cells (ID50 = 5.0 ppm) reflected primarily through cellular vacuole formation from dilation of rough endoplasmic reticulum structures. Similar vacuole formation was observed in E. tenella merozoites pulse-treated with the drug. This effect on both types of cells is prevented by SKF-525A, an inhibitor of microsomal drug metabolism. Drug-induced visible absorption difference spectra and alterations in the electron paramagnetic signal of rat liver microsomal cytochrome P-450 indicate direct bindings of arprinocid-1-N-oxide to cytochrome P-450. These findings suggest cytochrome P-450 mediated microsomal metabolism involving arprinocid-1-N-oxide as part of the mechanism of antococcidial action of the drug. This metabolism may cause destruction of endoplasmic reticulum leading to cell death.