Diphenylamine as an important structure of nonsteroidal anti-inflammatory drugs to uncouple mitochondrial oxidative phosphorylation

Biochem Pharmacol. 1999 Sep 1;58(5):861-5. doi: 10.1016/s0006-2952(99)00163-x.

Abstract

A marked difference has been observed in the inhibitory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on oxidative phosphorylation of rat liver mitochondria. It should be noted that some of the potent inhibitors, N-phenylanthranilic acids and diclofenac, have a similar "skeleton" structure, diphenylamine. Diphenylamine itself was found to inhibit oxidative phosphorylation significantly, although its inhibition potency was weaker than that of NSAIDs with a diphenylamine structure. In addition to decreases in the respiration control index (ratio of state 3 to state 4 respiration), these compounds released oligomycin-inhibited state 3 respiration. These results demonstrated that diphenylamine, as well as N-phenylanthranilic acids and diclofenac, was an uncoupler of oxidative phosphorylation of rat liver mitochondria. Thus, diphenylamine was suggested to play an important role in the uncoupling effects of NSAIDs with a diphenylamine skeleton.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Diphenylamine / chemistry
  • Diphenylamine / pharmacology*
  • In Vitro Techniques
  • Male
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / metabolism
  • Oxidation-Reduction
  • Phosphorylation / drug effects
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Diphenylamine