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Distribution of nitroreductive activity toward nilutamide in rat
Kjetil Ask1, Nathalie Décologne, Nana Asare
1Division 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. askkj@mcmaster.ca
Toxicology and Applied Pharmacology
|November 3, 2004
Summary
This study investigated nilutamide metabolism in rats, identifying nitroreductive activities in various tissues. These findings may explain side effects of this antiandrogen drug and other nitroaromatic compounds.
Area of Science:
- Pharmacology
- Toxicology
- Biochemistry
Background:
- Nilutamide is a nitroaromatic antiandrogen used for prostate cancer.
- Previous work identified lung nitroreductase activity.
- Nilutamide exhibits pneumotoxicity and hepatotoxicity.
Purpose of the Study:
- To characterize nilutamide metabolism across various rat tissues.
- To identify and differentiate nitroreductase activities (Type I and II).
- To explore potential mechanisms for nilutamide's side effects.
Main Methods:
- Collected tissue samples from male Sprague-Dawley rats (liver, brain, kidney, heart, lung, intestine, blood).
- Prepared subcellular fractions (cytosolic, microsomal) and processed intestinal contents.
- Assessed nitroreductase activity in the presence and absence of oxygen using HPLC analysis.
Main Results:
- Detected both cytosolic and microsomal Type II nitroreductase activities in all examined tissues.
- Observed Type I nitroreductase activity in lung, liver, kidney, and small intestine microsomes, and in intestinal lumen.
- Found highest nitroreductase activities in cytosols, which were oxygen-sensitive.
Conclusions:
- Characterized novel nitroreductive activities for nilutamide in rat tissues.
- Identified tissue-specific and oxygen-dependent nitroreductase activities.
- These metabolic pathways may contribute to the toxicity of nilutamide and related nitroaromatic drugs.