Inhibition of respiration by phenacetin in isolated tubules and mitochondria of rat kidney

Phenacetin. an analgesic drug thought to exert nephrotoxic effects in vivo, was found to inhibit respiration in isolated rat kidney tubules metabolizing endogenous substrate or exogenous glutamine, glucose or lactate. With isolated rat kidney mitochondria the oxidation of glutamate or succinate was strongly inhibited by phenacetin; in each case State 3 respiration and State 3u (uncoupled) respiration were affected to the same extent, indicating that phenacetin exerted its influence directly on the respiratory chain. The effects of phenacetin on the oxidation of NADH and succinate by submitochondrial particles in the presence of various electron acceptors suggested that at least two oxidoreduction reactions of the respiratory chain were susceptible to inhibition by phenacetin. One of these reactions was that catalysed by succinate dehydrogenase, while the other probably lay between reduced NADH dehydrogenase and coenzyme Q. The possibility that impairment to the oxygen-metabolising capacity of the kidney cell might contribute to the perceived cytotoxicity of phenacetin is discussed.