Denaturation of cytochrome P-450 by indomethacin and other non-steroidal antiinflammatory drugs: Evidence for a surfactant mechanism and a selective effect of a p-chlorophenyl moiety

Miriam Falzon, Andrea Nielsch, M. Danny Burke

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Indomethacin added to rat liver microsomes in vitro resulted in the denaturation of cytochrome P-450 to cytochrome P-420. This was NADPH independent, appeared to be non-enzyme mediated, did not involve free radicals or lipid peroxidation and was prevented by glycerol, butylated hydroxytoluene or SKF-525A. Indomethacin in vitro also caused a loss of cytochrome b5, NADH-cytochrome b5 reductase, NADPH-cytochrome c reductase and epoxide hydrolase activities, but an activation of UDP-glucuronyltransferase. Amongst a total of 22 non-steroidal anti-inflammatory drugs and derivatives there was a highly significant correlation between the extent of their denaturation of cytochrome P-450 and their surfactant potency. The results suggest that the denaturation of cytochrome P-450 by certain non-steroidal anti-inflammatory drugs was due to a detergent-like, membrane-perturbing action of the drugs and that in most cases the denaturation also involved a specific effect of a p-chlorophenyl moiety of the drug.

Original languageEnglish (US)
Pages (from-to)4019-4024
Number of pages6
JournalBiochemical Pharmacology
Volume35
Issue number22
DOIs
StatePublished - Nov 15 1986
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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