Ask Kjetil, Décologne Nathalie, Asare Nana, Holme Jørn A, Artur Yves, Pelczar Hélène, Camus Philippe
Division of Pulmonary and Intensive Care, and Laboratory of Pulmonary Pharmacology and Toxicology, Facultés de Médecine et de Pharmacie, UMR INRA/Université de Bourgogne 1234, 21000 Dijon, France.
Toxicol Appl Pharmacol. 2004 Nov 15;201(1):1-9. doi: 10.1016/j.taap.2004.04.006.
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.
尼鲁米特是一种具有肺毒性和肝毒性的硝基芳香族（R-NO2）抗雄激素药物，用于治疗男性前列腺癌。此前，我们已证实，在大鼠肺中，该药物可代谢为相应的羟胺（R-NHOH）和胺（R-NH2）衍生物。这些结果证明了肺中存在一种胞质氧敏感型（II型）硝基还原酶活性。在本研究中，我们扩展了对雄性Sprague-Dawley大鼠肝脏、脑、肾、心脏、血液、肠道（小肠、盲肠和大肠及其各自的管腔内容物）中尼鲁米特代谢的特征描述。通过差速超速离心法制备所有检测组织（血液除外）的亚细胞组分（线粒体后、胞质和微粒体）。血液和肠道内容物在检测前进行超声处理。在有或无氧气的条件下进行孵育，以评估I型和II型硝基还原酶活性。通过高效液相色谱法分析有机提取物，结果以每分钟每毫克蛋白质形成的R-NH2皮摩尔数表示。证实了四种不同的硝基还原活性。在所研究的所有组织样品中均检测到胞质和微粒体II型硝基还原酶活性。在任何胞质中均未观察到I型硝基还原酶活性，但在小肠、肺、肾和肝微粒体中检测到该活性。尼鲁米特在肠腔中也可被还原，可能是通过细菌I型硝基还原酶。在胞质中观察到最高活性，且对氧敏感。这些结果证明并描述了大鼠组织中以前未知的针对尼鲁米特的硝基还原活性，这可能为在人类治疗中观察到的尼鲁米特和其他硝基芳香族化合物的副作用提供一些解释。
