Induction of hepatic microsomal CYP4A activity and of peroxisomal beta-oxidation by two non-steroidal anti-inflammatory drugs.
The effects of the non-steroidal anti-inflammatory drugs fenbufen and ibuprofen on hepatic cytochrome P450 activities and peroxisomal proliferation were investigated in the rat, following intraperitoneal administration at three dose levels. At the two highest doses, 30 and 150 mg/kg, ibuprofen stimulated lauric acid hydroxylase activity but no other dose-dependent effects on cytochrome P450 activities were evident. Fenbufen, at the highest dose of 150 mg/kg, decreased cytochrome P450 content and related activities, and this effect was attributed to the toxicity of the drug at this dose. Immunoblot studies employing solubilized microsomes from ibuprofen-treated rats revealed that ibuprofen increased the apoprotein levels of CYP4A1, at the two higher doses. The same treatment with ibuprofen, at the highest dose only, increased the beta-oxidation of palmitoyl CoA, determined in liver homogenates, and immunoblott analysis showed an increase in the apoprotein levels of the trans-2-enoyl CoA hydratase trifunctional protein. Fenbufen did not influence palmitoyl beta-oxidation. Computer graphic overlays with clofibric acid showed that ibuprofen, when compared with fenbufen, displayed a better overall fit to clofibric acid. Finally, interaction energies between the two drugs and the putative peroxisome proliferator-activated receptor ligand domain revealed that ibuprofen had a higher affinity for the receptor than fenbufen, but the difference was modest. It is concluded that ibuprofen, at doses far exceeding those employed clinically, is a weak inducer of both CYP4A1 activity and peroxisomal proliferation and these effects may be attributed to the presence of an aryl propionic acid moiety.(ABSTRACT TRUNCATED AT 250 WORDS)
Rekka
E
E
Division of Toxicology, School of Biological Sciences, University of Surrey, Guildford, UK.
Ayalogu
E O
EO
Lewis
D F
DF
Gibson
G G
GG
Ioannides
C
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction; D007052:Ibuprofen / Q000494:pharmacology; D015151:Immunoblotting; D008297:Male; D008830:Microbodies / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism*; D010084:Oxidation-Reduction; D010654:Phenylbutyrates / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010654:Phenylbutyrates; D011422:Propionates; C011677:benoxaprofen; D003577:Cytochrome P-450 Enzyme System; C010725:fenbufen; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D007052:Ibuprofen