Effects of phenoperidine on rat liver mitochondrial respiration.

Phenoperidine decreases rat liver mitochondrial oxidation of the following substrates in state 3: glutamate, pyruvate/malate mixture, and succinate. The intensity of inhibition is dose-dependent and substrate-dependent. With glutamate which acts at the first phosphorylation site on the respiratory chain, phenoperidine seems to have two effects on mitochondrial oxidative processes: without preincubation, phenoperidine antagonizes mitochondrial oxidation of glutamate presumably by inhibiting enzymes involved in glutamate metabolism such as glutamate dehydrogenase and glutamate oxaloacetate transaminase. Upon a three min preincubation, an additional inhibitory mechanism develops: phenoperidine prevents glutamate from penetrating into the mitochondria. Inhibition without preincubation appears to be non competitive (K_i = 7.5 × 10^?5 M) and it is assumed that it takes place at a site before the 2,4-dinitrophenol (DNP)-sensitive site on the energy transfer process. In state 4, phenoperidine increases the oxidation of these substrates. It decreases the P/O ratio: thus it acts as an uncoupler, although not as potent as DNP. When compared with phenoperidine, levorphanol and pentazocine act as uncouplers but not as energy-transfer inhibitors. DALA-enkephalinamide increases state 4 respiration on glutamate. As for morphine, etorphine, meperidine and fentanyl, they do not act on mitochondrial processes. The effects of opiates on mitochondrial respiration are irrelevant to their morphinomimetic actions because they are not antagonized by naloxone.