Are the decreases in hepatic cytochrome P-450 and other drug-metabolising enzymes caused by indomethacin in vivo mediated by intestinal bacterial endotoxins?. 16,16-dimethylprostaglandin F prevents decreases in hepatic drug-metabolising enzymes due to exogenous endotoxin

Miriam Falzon, A. S. Milton, M. D. Burke

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24 Citations (Scopus)

Abstract

Administration of either indomethacin (8.5 mg/kg) or E. coli endotoxin (3.5 mg/kg) to rats caused significant decreases in a variety of drug-metabolising enzyme activities. Either agent markedly decreased biphenyl 4-hydroxylase by 72-80% and caused lesser decreases (21-64%) in cyt. P-450, aminopyrine N-demethylase, ethoxyresorufin O-deethylase (EROD), benzyloxyphenoxazone O-deben-zylase (BPOD), cyt. b5, NADPH-cyt. c reductase, NADH-cyt. b5 reductase, epoxide hydrolase (EH) and glucuronyl transferase (GT). The decreases in GT (21-22%) were significantly less than in cyt. P-450 (45-57%). Sulphotransferase was not affected by either indomethacin or endotoxin. The overall pattern of relative decreases in the different enzymes was similar for either indomethacin or endotoxin. Four activities, however, were affected to a significantly greater extent by indomethacin than by endotoxin at 2-6 mg/kg: EROD, BPOD, cyt. b5 and EH. Additionally, hepatic glutathione was decreased by indomethacin but not by endotoxin. Indomethacin or endotoxin caused similar but not identical decreases in selected protein bands in the "cyt. P-450 region" of microsomal SDS-polyacrylamide gel electrophoretograms. Concomitant administration of 16,16-dimethylprostaglandin F afforded significant (50-100%) protection against all the above-mentioned effects of indomethacin or endotoxin. The effects of indomethacin on cyt. P-450 were lessened by concomitant administration of a mixture of neomycin, polymyxin B and bacitracin. Throughout the study there was a close correlation between the extent of decrease in hepatic cyt. P-450 and the degree of intestinal ulceration caused by indomethacin. It was concluded that bacterial endotoxins liberated into the portal blood as a result of indomethacin-induced ulceration of the small intestine probably only partially mediated the effects of indomethacin on hepatic drug-metabolising enzymes. The protection afforded by 16,16-dimethylprostaglandin F could have been due to both the prevention of ulceration and to a direct cytoprotective effect on the liver.

Original languageEnglish (US)
Pages (from-to)1285-1292
Number of pages8
JournalBiochemical Pharmacology
Volume33
Issue number8
DOIs
StatePublished - Apr 15 1984
Externally publishedYes

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Endotoxins
Indomethacin
Cytochrome P-450 Enzyme System
Liver
Enzymes
Pharmaceutical Preparations
Epoxide Hydrolases
Cytochrome P-450 CYP1A1
Transferases
Oxidoreductases
Aminopyrine N-Demethylase
Sulfotransferases
Enzyme activity
NADP
NAD
Escherichia coli
Small Intestine
Glutathione
Rats
Blood

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{25f2ab62b3c342af8c658be60f8c0058,
title = "Are the decreases in hepatic cytochrome P-450 and other drug-metabolising enzymes caused by indomethacin in vivo mediated by intestinal bacterial endotoxins?. 16,16-dimethylprostaglandin F2α prevents decreases in hepatic drug-metabolising enzymes due to exogenous endotoxin",
abstract = "Administration of either indomethacin (8.5 mg/kg) or E. coli endotoxin (3.5 mg/kg) to rats caused significant decreases in a variety of drug-metabolising enzyme activities. Either agent markedly decreased biphenyl 4-hydroxylase by 72-80{\%} and caused lesser decreases (21-64{\%}) in cyt. P-450, aminopyrine N-demethylase, ethoxyresorufin O-deethylase (EROD), benzyloxyphenoxazone O-deben-zylase (BPOD), cyt. b5, NADPH-cyt. c reductase, NADH-cyt. b5 reductase, epoxide hydrolase (EH) and glucuronyl transferase (GT). The decreases in GT (21-22{\%}) were significantly less than in cyt. P-450 (45-57{\%}). Sulphotransferase was not affected by either indomethacin or endotoxin. The overall pattern of relative decreases in the different enzymes was similar for either indomethacin or endotoxin. Four activities, however, were affected to a significantly greater extent by indomethacin than by endotoxin at 2-6 mg/kg: EROD, BPOD, cyt. b5 and EH. Additionally, hepatic glutathione was decreased by indomethacin but not by endotoxin. Indomethacin or endotoxin caused similar but not identical decreases in selected protein bands in the {"}cyt. P-450 region{"} of microsomal SDS-polyacrylamide gel electrophoretograms. Concomitant administration of 16,16-dimethylprostaglandin F2α afforded significant (50-100{\%}) protection against all the above-mentioned effects of indomethacin or endotoxin. The effects of indomethacin on cyt. P-450 were lessened by concomitant administration of a mixture of neomycin, polymyxin B and bacitracin. Throughout the study there was a close correlation between the extent of decrease in hepatic cyt. P-450 and the degree of intestinal ulceration caused by indomethacin. It was concluded that bacterial endotoxins liberated into the portal blood as a result of indomethacin-induced ulceration of the small intestine probably only partially mediated the effects of indomethacin on hepatic drug-metabolising enzymes. The protection afforded by 16,16-dimethylprostaglandin F2α could have been due to both the prevention of ulceration and to a direct cytoprotective effect on the liver.",
author = "Miriam Falzon and Milton, {A. S.} and Burke, {M. D.}",
year = "1984",
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TY - JOUR

T1 - Are the decreases in hepatic cytochrome P-450 and other drug-metabolising enzymes caused by indomethacin in vivo mediated by intestinal bacterial endotoxins?. 16,16-dimethylprostaglandin F2α prevents decreases in hepatic drug-metabolising enzymes due to exogenous endotoxin

AU - Falzon, Miriam

AU - Milton, A. S.

AU - Burke, M. D.

PY - 1984/4/15

Y1 - 1984/4/15

N2 - Administration of either indomethacin (8.5 mg/kg) or E. coli endotoxin (3.5 mg/kg) to rats caused significant decreases in a variety of drug-metabolising enzyme activities. Either agent markedly decreased biphenyl 4-hydroxylase by 72-80% and caused lesser decreases (21-64%) in cyt. P-450, aminopyrine N-demethylase, ethoxyresorufin O-deethylase (EROD), benzyloxyphenoxazone O-deben-zylase (BPOD), cyt. b5, NADPH-cyt. c reductase, NADH-cyt. b5 reductase, epoxide hydrolase (EH) and glucuronyl transferase (GT). The decreases in GT (21-22%) were significantly less than in cyt. P-450 (45-57%). Sulphotransferase was not affected by either indomethacin or endotoxin. The overall pattern of relative decreases in the different enzymes was similar for either indomethacin or endotoxin. Four activities, however, were affected to a significantly greater extent by indomethacin than by endotoxin at 2-6 mg/kg: EROD, BPOD, cyt. b5 and EH. Additionally, hepatic glutathione was decreased by indomethacin but not by endotoxin. Indomethacin or endotoxin caused similar but not identical decreases in selected protein bands in the "cyt. P-450 region" of microsomal SDS-polyacrylamide gel electrophoretograms. Concomitant administration of 16,16-dimethylprostaglandin F2α afforded significant (50-100%) protection against all the above-mentioned effects of indomethacin or endotoxin. The effects of indomethacin on cyt. P-450 were lessened by concomitant administration of a mixture of neomycin, polymyxin B and bacitracin. Throughout the study there was a close correlation between the extent of decrease in hepatic cyt. P-450 and the degree of intestinal ulceration caused by indomethacin. It was concluded that bacterial endotoxins liberated into the portal blood as a result of indomethacin-induced ulceration of the small intestine probably only partially mediated the effects of indomethacin on hepatic drug-metabolising enzymes. The protection afforded by 16,16-dimethylprostaglandin F2α could have been due to both the prevention of ulceration and to a direct cytoprotective effect on the liver.

AB - Administration of either indomethacin (8.5 mg/kg) or E. coli endotoxin (3.5 mg/kg) to rats caused significant decreases in a variety of drug-metabolising enzyme activities. Either agent markedly decreased biphenyl 4-hydroxylase by 72-80% and caused lesser decreases (21-64%) in cyt. P-450, aminopyrine N-demethylase, ethoxyresorufin O-deethylase (EROD), benzyloxyphenoxazone O-deben-zylase (BPOD), cyt. b5, NADPH-cyt. c reductase, NADH-cyt. b5 reductase, epoxide hydrolase (EH) and glucuronyl transferase (GT). The decreases in GT (21-22%) were significantly less than in cyt. P-450 (45-57%). Sulphotransferase was not affected by either indomethacin or endotoxin. The overall pattern of relative decreases in the different enzymes was similar for either indomethacin or endotoxin. Four activities, however, were affected to a significantly greater extent by indomethacin than by endotoxin at 2-6 mg/kg: EROD, BPOD, cyt. b5 and EH. Additionally, hepatic glutathione was decreased by indomethacin but not by endotoxin. Indomethacin or endotoxin caused similar but not identical decreases in selected protein bands in the "cyt. P-450 region" of microsomal SDS-polyacrylamide gel electrophoretograms. Concomitant administration of 16,16-dimethylprostaglandin F2α afforded significant (50-100%) protection against all the above-mentioned effects of indomethacin or endotoxin. The effects of indomethacin on cyt. P-450 were lessened by concomitant administration of a mixture of neomycin, polymyxin B and bacitracin. Throughout the study there was a close correlation between the extent of decrease in hepatic cyt. P-450 and the degree of intestinal ulceration caused by indomethacin. It was concluded that bacterial endotoxins liberated into the portal blood as a result of indomethacin-induced ulceration of the small intestine probably only partially mediated the effects of indomethacin on hepatic drug-metabolising enzymes. The protection afforded by 16,16-dimethylprostaglandin F2α could have been due to both the prevention of ulceration and to a direct cytoprotective effect on the liver.

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