title: Metabolism of nilutamide in rat lung.
abstract: Nilutamide is a non-steroidal anti-androgen drug proposed in the treatment of metastatic prostatic carcinoma. Its therapeutic effects are overshadowed by the occurrence of adverse reactions, mediated by mechanisms that remain elusive. To elucidate possible mechanisms for nilutamide toxicity, we investigated the metabolism of nilutamide in rat lung homogenates, in subcellular fractions and in freshly isolated cells. In whole lung homogenates, the nitro group of nilutamide was reduced to the amine and hydroxylamine moieties. These conversions occurred exclusively in the absence of dioxygen, were increased by the addition of FMN, FAD, or NADPH. Reductive metabolism of nilutamide to the amine and hydroxylamine was further evidenced in subcellular fractions obtained by differential ultracentrifugation. It was found to take place mainly in the cytosol of rat lung and to be stimulated, strongly, upon co-addition of NADPH and FMN. Addition of inhibitors of enzymes involved in the reductive metabolism of nitroaromatic compounds indicated that reduction of nilutamide involved, mainly, soluble flavoproteins. Incubations with freshly isolated lung cells revealed that macrophages were the main players in nitroreduction of nilutamide whereas the epithelial type II cells and the non-ciliated Clara cells were less efficient in catalyzing this reaction. Our results show that nilutamide is extensively reduced by lung tissues in the absence of oxygen, especially by enzymes found in alveolar macrophages. In accordance with recent findings, subcellular localization, oxygen sensitivity, cofactor requirements and inhibitor studies lead us to suggest the involvement of a soluble nitric oxide synthase in lung cytosolic nitroreduction.
authors.affiliation: Laboratory of Pulmonary Pharmacology and Toxicology, UMR INRA/Université de Bourgogne 1234, Faculté de Médecine et de Pharmacie, Dijon, France. askkj@mcmaster.ca
authors.forename: Kjetil
authors.initials: K
authors.lastname: Ask
authors.forename: Nathalie
authors.initials: N
authors.lastname: Décologne
authors.forename: Christian
authors.initials: C
authors.lastname: Ginies
authors.forename: Marit
authors.initials: M
authors.lastname: Låg
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Boucher
authors.forename: Jørn A
authors.initials: JA
authors.lastname: Holme
authors.forename: Hélène
authors.initials: H
authors.lastname: Pelczar
authors.forename: Philippe
authors.initials: P
authors.lastname: Camus
mesh_terms: D000726:Androgen Antagonists / Q000378:metabolism*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D048289:Imidazolidines / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000726:Androgen Antagonists; D004791:Enzyme Inhibitors; D048289:Imidazolidines; C021277:nilutamide