INTEREST OF ESR IN DETERMINING THE MECHANISMS OF DRUG TOXICITY - APPLICATION TO THE ANTIANDROGEN NILUTAMIDE

The antiandrogen nilutamide is a nitroarene utilised in the treatment of metastatic prostatic carcinoma. The side effects of nilutamide include drug-induced acute hepatitis and pulmonary fibrosis. Using ESR, we showed that NADPH-cytochrome P-450 reductase catalysed the one-electron reduction of nilutamide to the corresponding nitroanion free radical in rat lung microsomes and in rat liver mirosomes. Under anaerobic conditions, further reductions of the nitroanion free radical led to the formation of reactive species (i.e. the nitroso and the hydroxylamine) which covalently bound to cellular macromolecules. Under aerobic conditions, the nitroanion free radical reacted with oxygen and formed a redox cycle which resulted in the formation of great amounts of reactive oxygen species (ie. superoxyde anion and hydrogen peroxide). Such reactive oxygen species were responsible for the toxicity of nilutamide towards rat isolated hepatocytes.