Induction of hepatic microsomal CYP4A activity and of peroxisomal β-oxidation by two non-steroidal anti-inflammatory drugs

Abstract

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)

Stress and Active Oxygen Species – Effect of α‐Tocopherol on Stress Response

“…Although corticosterone is not generally considered to be a potent inducer [7,35], it preferably induces CYP3A1 like other steroids [36]. This is further supported by the fact that the N-demethylation of erythromycin, a specific substrate for CYP3A [37], is greatly augmented under stress conditions [38].…”

“…However, the augmented metabolism of erythromycin and 4-nitrophenol, CYP3A1 and CYP2E1 substrates, respec-tively [41,37], indicates that both the above isoenzymes are induced in stressful conditions.…”

Induction of Cyclooxygenase-2 Expression by Peroxisome Proliferators and Non-tetradecanoylphorbol 12,13-Myristate-type Tumor Promoters in Immortalized Mouse Liver Cells

“…These concentrations of indomethacin are 50 -100-fold greater than required for cyclooxygenase inhibition, indicating that induction of COX-2 expression is not a consequence of inhibited cyclooxygenase activity. The fact that indomethacin at high doses behaved like the PPs in inducing COX-2 expression is not surprising given the structural similarity of many NSAIDS to peroxisome proliferators (44,45).…”

“…The NSAID indomethacin, itself a peroxisome proliferator (44,45), completely inhibited PGE 2 synthesis at a dose of 10 M but required 500-1000 M to induce strong COX-2 expression. Induction of COX-2 by NSAIDS has been reported previously (49) and is consistent with the structural similarity between PPs and NSAIDS (44,45). Thus, COX-2 induction by PPs is probably not a consequence of inhibited prostaglandin synthesis, but rather is probably due to the activation of immediate-early signaling pathways (36).…”

Dose of Phenobarbital and Age of Treatment at Early Life are Two Key Factors for the Persistent Induction of Cytochrome P450 Enzymes in Adult Mouse Liver

“…Some drugs can serve as ligands to activate nuclear receptors and induce the expression of P450 genes in human hepatocytes (Handschin and Meyer, 2003). For example, constitutive androstane receptor (CAR) can be activated by phenobarbital (Gervot et al, 1999;Sueyoshi et al, 1999) and phenytoin (Wang et al, 2004), pregnane X receptor by rifampicin (Goodwin et al, 1999(Goodwin et al, , 2001Gorski et al, 2003;Chen et al, 2004) and hyperforin (Chen et al, 2004), glucocorticoid receptor (GR) by dexamethasone (Onica et al, 2008), aryl hydrocarbon receptor by omeprazole (Gerbal-Chaloin et al, 2006), and peroxisome proliferatoractivated receptor g by ibuprofen (Rekka et al, 1994).…”