TY - JOUR
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
N1 - Funding Information:
* Current address: Building 37, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. U.S.A. f Author to whom all correspondence should be addressed. + Abbreviations: NSAID. non-steroidal anti-inflam-mitory drug; DMI, 0-desmethylindomethacin; DBI, N-desbenzoylindomethacin; DMBI, O-desmethyl-N-desben-zoylindomethacin; CBA,p-chlorobenzoic acid; SKF-525A. diethylaminoethyl diphenylpropylacetate; EDTA, ethylenediaminetetracetic acid; BHT, butylated hydroxytoluene; PG. prostaglandin.
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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U2 - 10.1016/0006-2952(86)90021-3
DO - 10.1016/0006-2952(86)90021-3
M3 - Article
C2 - 3778523
AN - SCOPUS:0023003385
SN - 0006-2952
VL - 35
SP - 4019
EP - 4024
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 22
ER -