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Activating effect of benzbromarone, a uricosuric drug, on peroxisome proliferator-activated receptors.

Kunishima C, Inoue I, Oikawa T, Nakajima H, Komoda T, Katayama S - PPAR Res (2007)

Bottom Line: To elucidate the mechanisms underlying induction of peroxisome proliferation by benzbromarone, we examined binding affinity for peroxisome proliferator-activated receptor alpha (PPARalpha) and gamma (PPARgamma), and effects on the binding activity of PPARs with peroxisome proliferation-responsive element (PPRE) and expression of the PPARs target protein.Furthermore, cultured cells with benzbromarone added showed upregulated expression of LPL and ACS.These results suggest that benzbromarone induces peroxisome proliferation in hepatocytes by binding to PPARs, and controls expression of proteins related to lipid metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacovigilance, Torii Pharmaceutical Co., Ltd., 3-4-1 Nihonbashi-honcho, Chuo-ku, Tokyo 103-8439, Japan.

ABSTRACT
Benzbromarone, a uricosuric drug, reportedly causes hepatic hypertrophy accompanied by proliferation of peroxisomes in rats. To elucidate the mechanisms underlying induction of peroxisome proliferation by benzbromarone, we examined binding affinity for peroxisome proliferator-activated receptor alpha (PPARalpha) and gamma (PPARgamma), and effects on the binding activity of PPARs with peroxisome proliferation-responsive element (PPRE) and expression of the PPARs target protein. Binding affinity of benzbromarone for PPARalpha and PPARgamma was examined by reporter gene assay. Binding activity of PPARs with PPRE was determined by electric mobility shift assay, and expression of lipoprotein lipase (LPL) and acyl-CoA synthetase (ACS) by Western blot method. Benzbromarone displayed affinity for PPARalpha and PPARgamma, and promoted binding of PPARs to PPRE. Furthermore, cultured cells with benzbromarone added showed upregulated expression of LPL and ACS. These results suggest that benzbromarone induces peroxisome proliferation in hepatocytes by binding to PPARs, and controls expression of proteins related to lipid metabolism.

No MeSH data available.


Related in: MedlinePlus

Effects of benzbromarone (•), troglitazone (∘), pioglitazone (▪),fenofibric acid (□), and clofibric acid (Δ) on PPARα activation. Cells were transfected with the receptor plasmid for the chimera of the PPARα ligand-binding domain and GAL4 DNA-binding domain, together with a reporter plasmid containing a GAL4-responsive promoter driving the expression of luciferase. Each point represents mean ± standard deviation (SD).
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fig1: Effects of benzbromarone (•), troglitazone (∘), pioglitazone (▪),fenofibric acid (□), and clofibric acid (Δ) on PPARα activation. Cells were transfected with the receptor plasmid for the chimera of the PPARα ligand-binding domain and GAL4 DNA-binding domain, together with a reporter plasmid containing a GAL4-responsive promoter driving the expression of luciferase. Each point represents mean ± standard deviation (SD).

Mentions: The binding affinity of benzbromarone for PPARα andPPARγ was examined by reporter gene assay using transcriptional activity of the PPAR target gene as a marker, in comparison with those of clofibric acid, fenofibric acid, troglitazone, andpioglitazone (Figures 1 and 2). At 100 μM, benzbromarone induced an increase in luciferase activity, representingtranscriptional activation of the target gene via binding of benzbromarone to PPARα, and the magnitude was nearly equal to that induced by clofibric acid,while fenofibric acid and pioglitazone induced transcriptional activation of the target gene at concentrations of  μM. Against PPARγ,benzbromarone induced an increase in luciferase activity at a concentration of100 μM, troglitazone at  μM, and pioglitazone at  μM.


Activating effect of benzbromarone, a uricosuric drug, on peroxisome proliferator-activated receptors.

Kunishima C, Inoue I, Oikawa T, Nakajima H, Komoda T, Katayama S - PPAR Res (2007)

Effects of benzbromarone (•), troglitazone (∘), pioglitazone (▪),fenofibric acid (□), and clofibric acid (Δ) on PPARα activation. Cells were transfected with the receptor plasmid for the chimera of the PPARα ligand-binding domain and GAL4 DNA-binding domain, together with a reporter plasmid containing a GAL4-responsive promoter driving the expression of luciferase. Each point represents mean ± standard deviation (SD).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2233808&req=5

fig1: Effects of benzbromarone (•), troglitazone (∘), pioglitazone (▪),fenofibric acid (□), and clofibric acid (Δ) on PPARα activation. Cells were transfected with the receptor plasmid for the chimera of the PPARα ligand-binding domain and GAL4 DNA-binding domain, together with a reporter plasmid containing a GAL4-responsive promoter driving the expression of luciferase. Each point represents mean ± standard deviation (SD).
Mentions: The binding affinity of benzbromarone for PPARα andPPARγ was examined by reporter gene assay using transcriptional activity of the PPAR target gene as a marker, in comparison with those of clofibric acid, fenofibric acid, troglitazone, andpioglitazone (Figures 1 and 2). At 100 μM, benzbromarone induced an increase in luciferase activity, representingtranscriptional activation of the target gene via binding of benzbromarone to PPARα, and the magnitude was nearly equal to that induced by clofibric acid,while fenofibric acid and pioglitazone induced transcriptional activation of the target gene at concentrations of  μM. Against PPARγ,benzbromarone induced an increase in luciferase activity at a concentration of100 μM, troglitazone at  μM, and pioglitazone at  μM.

Bottom Line: To elucidate the mechanisms underlying induction of peroxisome proliferation by benzbromarone, we examined binding affinity for peroxisome proliferator-activated receptor alpha (PPARalpha) and gamma (PPARgamma), and effects on the binding activity of PPARs with peroxisome proliferation-responsive element (PPRE) and expression of the PPARs target protein.Furthermore, cultured cells with benzbromarone added showed upregulated expression of LPL and ACS.These results suggest that benzbromarone induces peroxisome proliferation in hepatocytes by binding to PPARs, and controls expression of proteins related to lipid metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacovigilance, Torii Pharmaceutical Co., Ltd., 3-4-1 Nihonbashi-honcho, Chuo-ku, Tokyo 103-8439, Japan.

ABSTRACT
Benzbromarone, a uricosuric drug, reportedly causes hepatic hypertrophy accompanied by proliferation of peroxisomes in rats. To elucidate the mechanisms underlying induction of peroxisome proliferation by benzbromarone, we examined binding affinity for peroxisome proliferator-activated receptor alpha (PPARalpha) and gamma (PPARgamma), and effects on the binding activity of PPARs with peroxisome proliferation-responsive element (PPRE) and expression of the PPARs target protein. Binding affinity of benzbromarone for PPARalpha and PPARgamma was examined by reporter gene assay. Binding activity of PPARs with PPRE was determined by electric mobility shift assay, and expression of lipoprotein lipase (LPL) and acyl-CoA synthetase (ACS) by Western blot method. Benzbromarone displayed affinity for PPARalpha and PPARgamma, and promoted binding of PPARs to PPRE. Furthermore, cultured cells with benzbromarone added showed upregulated expression of LPL and ACS. These results suggest that benzbromarone induces peroxisome proliferation in hepatocytes by binding to PPARs, and controls expression of proteins related to lipid metabolism.

No MeSH data available.


Related in: MedlinePlus