Decreased hepatic microsomal cytochrome P450 due to indomethacin

Protective roles of 16,16-dimethylprostaglandin F and inducing agents

M. Danny Burke, Miriam Falzon, Anthony S. Milton

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Indomethacin administration to rats caused a dose-dependent decrease in hepatic microsomal cytochrome P450, aminopyrine N-demethylase, ethoxyresorufin O-de-ethylase and benzyloxyresorufin O-debenzylase, accompanied by selective alterations in microsomal sodium dodecylsulphate polyacrylamide gel electrophoretograms. High doses ({slanted equal to or greater-than}8.5 mg/kg) caused the disappearance of certain of the SDS-PAGE proteins tentatively identified as being different forms of cyt. P450, together with either increases, decreases or no change in some of the non-cyt. P450 proteins in the electrophoretogram. Concomitant administration of 16,16-dimethylprostaglandin F gave dose-dependent protection against the deleterious effects of indomethacin on the enzymic and electrophoretic parameters of cyt. P450, but did not prevent the changes due to indomethacin in the non-cyt. P450 proteins on the electrophoretogram. In contrast, prior phenobarbitone or 3-methylcholanthrene induction prevented the effects of indomethacin on both cyt. P450 and the other microsomal proteins. Concomitant administration of SKF-525A exacerbated the effects of indomethacin on cyt. P450 and the other proteins. Indomethacin coadministration with 3-methylcholanthrene resulted in the major 3MC-induced putative cyt. P450 apoprotein having a lower mol. wt than usual. Conversely, indomethacin did not prevent the induction by SKF-525A of a different putative cyt. P450 apoprotein, despite causing decreases in cyt. P450 as determined spectrophotometrically and enzymologically. The results indicate that indomethacin rather than one of its metabolites is responsible for the decrease in cyt. P450 and that the mechanisms of protection by prostaglandin and inducing agents are, respectively, different.

Original languageEnglish (US)
Pages (from-to)389-397
Number of pages9
JournalBiochemical Pharmacology
Volume32
Issue number3
DOIs
StatePublished - Feb 1 1983
Externally publishedYes

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Indomethacin
Cytochrome P-450 Enzyme System
Liver
Proadifen
Apoproteins
Methylcholanthrene
Proteins
Aminopyrine N-Demethylase
Phenobarbital
Metabolites
Prostaglandins
Rats
Polyacrylamide Gel Electrophoresis
Sodium

ASJC Scopus subject areas

  • Pharmacology

Cite this

Decreased hepatic microsomal cytochrome P450 due to indomethacin : Protective roles of 16,16-dimethylprostaglandin F and inducing agents. / Burke, M. Danny; Falzon, Miriam; Milton, Anthony S.

In: Biochemical Pharmacology, Vol. 32, No. 3, 01.02.1983, p. 389-397.

Research output: Contribution to journalArticle

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abstract = "Indomethacin administration to rats caused a dose-dependent decrease in hepatic microsomal cytochrome P450, aminopyrine N-demethylase, ethoxyresorufin O-de-ethylase and benzyloxyresorufin O-debenzylase, accompanied by selective alterations in microsomal sodium dodecylsulphate polyacrylamide gel electrophoretograms. High doses ({slanted equal to or greater-than}8.5 mg/kg) caused the disappearance of certain of the SDS-PAGE proteins tentatively identified as being different forms of cyt. P450, together with either increases, decreases or no change in some of the non-cyt. P450 proteins in the electrophoretogram. Concomitant administration of 16,16-dimethylprostaglandin F2α gave dose-dependent protection against the deleterious effects of indomethacin on the enzymic and electrophoretic parameters of cyt. P450, but did not prevent the changes due to indomethacin in the non-cyt. P450 proteins on the electrophoretogram. In contrast, prior phenobarbitone or 3-methylcholanthrene induction prevented the effects of indomethacin on both cyt. P450 and the other microsomal proteins. Concomitant administration of SKF-525A exacerbated the effects of indomethacin on cyt. P450 and the other proteins. Indomethacin coadministration with 3-methylcholanthrene resulted in the major 3MC-induced putative cyt. P450 apoprotein having a lower mol. wt than usual. Conversely, indomethacin did not prevent the induction by SKF-525A of a different putative cyt. P450 apoprotein, despite causing decreases in cyt. P450 as determined spectrophotometrically and enzymologically. The results indicate that indomethacin rather than one of its metabolites is responsible for the decrease in cyt. P450 and that the mechanisms of protection by prostaglandin and inducing agents are, respectively, different.",
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