Denaturation of cytochrome P-450 by indomethacin and other non-steroidal anti-inflammatory drugs: evidence for a surfactant mechanism and a selective effect of a p-chlorophenyl moiety.
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.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D003580:Cytochromes / Q000032:analysis; D007213:Indomethacin / Q000494:pharmacology*; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D011489:Protein Denaturation; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003580:Cytochromes; D008054:Lipid Peroxides; D013501:Surface-Active Agents; C013464:cytochrome P420; D003577:Cytochrome P-450 Enzyme System; D007213:Indomethacin