Inhibition by nilutamide of the mitochondrial respiratory chain and ATP formation. Possible contribution to the adverse effects of this antiandrogen.
The effects of nilutamide on the mitochondrial respiratory chain were investigated in rats. In isolated mitochondria, nilutamide (100 microM) inhibited respiration that was supported by substrates feeding electrons into complex I of the respiratory chain but did not inhibit respiration that was supported by substrates donating electrons to complexes II, III or IV. Inhibition of complex I occurred without any lag time. In submitochondrial particles, nilutamide (100 microM) decreased both oxygen consumption mediated by NADH and the oxidation of NADH; addition of superoxide dismutase and catalase did not alleviate inhibition. There was no electron spin resonance evidence for detectable mitochondrial formation of the nilutamide nitro anion free radical by submitochondrial particles or for the formation of iron-nitrosyl complexes with mitochondrial Fe-S clusters in isolated hepatocytes. Severe inhibition of complex I by nilutamide (500 microM) led to upstream inhibition of fatty acid beta-oxidation. Nilutamide (100 microM) decreased the mitochondrial membrane potential and ATP formation in mitochondria energized by malate plus glutamate. In hepatocytes incubated without glucose, nilutamide (500 microM) led to an early (2 hr) drop in cellular ATP and early (4 hr) toxicity. With 5 mM glucose, however, ATP was not decreased and toxicity was mild at these early times. It was concluded that nilutamide itself inhibited the mitochondrial respiratory chain at the level of complex I and decreased ATP in hepatocytes incubated without glucose, which resulted in early toxicity. In the presence of glucose, ATP was not depleted at early times and delayed toxicity was probably the result of an oxidative stress (as previously reported).
Unité de Recherches de Physiopathologie Hépatique (Institut National de la Santé et de la Recherche Médicale U-24, Hôpital Beaujon, Clichy, France.
A
A
Berson
L
L
Schmets
C
C
Fisch
D
D
Fau
C
C
Wolf
B
B
Fromenty
D
D
Deschamps
D
D
Pessayre
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004072:Digitonin / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D007093:Imidazoles / Q000633:toxicity*; D048289:Imidazolidines; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects*; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000726:Androgen Antagonists; D002250:Carbon Radioisotopes; D007093:Imidazoles; D048289:Imidazolidines; D010169:Palmitic Acids; D002245:Carbon Dioxide; D019308:Palmitic Acid; C021277:nilutamide; D000255:Adenosine Triphosphate; D004072:Digitonin