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 Citations (Scopus)

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

Fingerprint

Denaturation
Surface-Active Agents
Indomethacin
Cytochrome P-450 Enzyme System
Anti-Inflammatory Agents
Pharmaceutical Preparations
Cytochrome-B(5) Reductase
Proadifen
Epoxide Hydrolases
Cytochromes b5
Butylated Hydroxytoluene
Glucuronosyltransferase
NADPH-Ferrihemoprotein Reductase
Uridine Diphosphate
Liver Microsomes
NADP
Detergents
Liver
Glycerol
Lipid Peroxidation

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "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",
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.",
author = "Miriam Falzon and Andrea Nielsch and Burke, {M. Danny}",
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T1 - Denaturation of cytochrome P-450 by indomethacin and other non-steroidal antiinflammatory drugs

T2 - Evidence for a surfactant mechanism and a selective effect of a p-chlorophenyl moiety

AU - Falzon, Miriam

AU - Nielsch, Andrea

AU - Burke, M. Danny

PY - 1986/11/15

Y1 - 1986/11/15

N2 - 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.

AB - 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.

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