Nilutamide is a pneumotoxic and hepatotoxic nitroaromatic (R-NO2)
antiandrogen used in the treatment of prostate
carcinoma in man. Previously, we established that in the rat lung, the
drug is metabolized into the corresponding
hydroxylamine (R-NHOH) and
amine (R-NH2) derivatives. These results evidenced a cytosolic
oxygen-sensitive (type II)
nitroreductase activity in lung. In the present studies, we extended the characterization of
nilutamide metabolism in liver, brain, kidney, heart, blood, intestine (small, cecum, and large, and their respective
luminal contents) of male Sprague-Dawley rats. Subcellular fractions for all tissues (except blood) examined (postmitochondrial, cytosolic, and microsomal) were prepared by differential ultracentrifugation. Blood and intestinal contents were sonicated before investigation. Incubations were run in the presence or absence of O2 to assess type I and II
nitroreductase activities. Organic extracts were analyzed by HPLC methods and results were expressed as pmoles of R-NH2 formed per milligram
protein per minute. Four distinct nitroreductive activities were evidenced. Cytosolic and microsomal type II
nitroreductase activities were detected in all tissue samples studied. Type I NR activity was not observed in any of the cytosols, but was detected in the small intestine, lung, kidney, and liver microsomes.
Nilutamide was also reduced in the intestinal lumen, possibly by a bacterial type I
nitroreductase. Highest activities were observed in cytosols and were
oxygen sensitive. These results evidence and characterize previously unknown nitroreductive activities toward
nilutamide in rat tissues that might provide some explanation to the side effects of
nilutamide and other nitroaromatic compounds observed in human
therapeutics.