Effects of Benzbromarone and Allopurinol on Adiponectin In Vivo and In Vitro

Abstract

When treating gout patients, we have incidentally found elevated serum levels of adiponectin in some after administration of benzbromarone. In the present study, we determined whether benzbromarone increases the serum level of adiponectin in gout patients and investigated the mechanism involved. Sixty-nine patients with gout were separated into two groups, and then treated for 1 year with uric acid-lowering therapy using benzbromarone or allopurinol. After overnight fasting, blood samples were drawn before and at 1 year after beginning of treatment. In an in vitro study, 3T3L1 cells were incubated in medium containing benzbromarone, allopurinol, pioglitazone, or uric acid, after which real time PCR assays were performed for messenger RNA of adiponectin, aP2, and CD36. Furthermore, 3T3L1 cells were incubated in medium containing GW9662 (PPARγ antagonist) together with benzbromarone or pioglitazone, after which real-time PCR assays were performed for messenger RNA of adiponectin. In the in vivo study, benzbromarone increased the serum concentration of adiponectin in the subjects, whereas allopurinol did not. In vitro, benzbromarone and pioglitazone each increased the levels of messenger RNA of adiponectin, aP2, and CD36 in 3T3 cells, whereas allopurinol and uric acid did not. Also, GW9662 suppressed the increase in adiponectin mRNA induced by benzbromarone as well as that by pioglitazone. Together, our results suggest that benzbromarone enhances the production of adiponectin via activation of PPARγ, which is a weak agonist for PPARγ.

Key words

adiponectin - benzbromarone - aP2 - CD36 - PPARγ

References

• 1 Zaka R, Williams CJ. New developments in the epidemiology and genetics of gout.  Curr Rheumatol Rep. 2006;  8 215-223
• 2 ATP Final Report . Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.  Circulation. 2002;  106 3143-3421
• 3 Alberti KG, Zimmet P, Shaw J. IDF Epidemiology Task Force Consensus Group . The metabolic syndrome – a new worldwide definition.  Lancet. 2005;  366 1059-1062
• 4 Takahashi S, Yamamoto T, Tsutsumi Z, Moriwaki Y, Yamakita J, Higashino K. Close correlation between visceral fat accumulation and uric acid metabolism in healthy men.  Metabolism. 1997;  46 1162-1165
• 5 Takahashi S, Moriwaki Y, Tsutsumi Z, Yamakita J, Yamamoto T, Hada T. Increased visceral fat accumulation further aggravates the risks of insulin resistance in gout.  Metabolism. 2001;  50 393-398
• 6 Yamamoto T, Moriwaki Y, Ka T, Inokuchi T, Takahashi S, Tsutsumi Z, Fukuchi M, Hada T. Effect of purine-free low-malt liquor (happo-shu) on the plasma concentrations and urinary excretion of purine bases and uridine–comparison between purine-free and regular happo-shu.  Horm Metab Res. 2004;  36 231-237
• 7 Heel RC, Brogden RN, Speight TM, Avery GS. Benzbromarone: a review of its pharmacological properties and therapeutic use in gout and hyperuricaemia.  Drugs. 1977;  14 349-366
• 8 Klauw MM van der, Houtman PM, Stricker BH, Spoelstra P. Hepatic injury caused by benzbromarone.  J Hepatol. 1994;  20 376-379
• 9 Emmerson BT. The use of the xanthine oxidase inhibitor, allopurinol, in the control of hyperuricaemia, gout and uric acid calculi.  Australas Ann Med. 1967;  16 205-214
• 10 Fischer-Posovszky P, Wabitsch M, Hochberg Z. Endocrinology of adipose tissue – an update.  Horm Metab Res. 2007;  39 314-321
• 11 Wallace SL, Robinson H, Masi AT, Decker JL, MacCarty DJ, Yü T-F. Preliminary criteria for the classification of the acute arthritis of primary gout.  Arthritis Rheum. 1977;  20 895-900
• 12 Fujimoto M, Masuzaki H, Tanaka T, Yasue S, Tomita T, Okazawa K, Fujikura J, Chusho H, Ebihara K, Hayashi T, Hosoda K, Nakao K. An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes.  FEBS Lett. 2004;  576 492-497
• 13 Inokuchi T, Moriwaki Y, Tsutsui H, Yamamoto A, Takahashi S, Tsutsumi Z, Ka T, Nakanishi K, Yamamoto T. Plasma interleukin (IL)-18 (interferon-gamma-inducing factor) and other inflammatory cytokines in patients with gouty arthritis and monosodium urate monohydrate crystal-induced secretion of IL-18.  Cytokine. 2006;  33 21-27
• 14 Arai N, Masuzaki H, Tanaka T, Ishii T, Yasue S, Kobayashi N, Tomita T, Noguchi M, Kusakabe T, Fujikura J, Ebihara K, Hirata M, Hosoda K, Hayashi T, Sawai H, Minokoshi Y, Nakao K. Ceramide and adenosine 5′-monophosphate-activated protein kinase are two novel regulators of 11beta-hydroxysteroid dehydrogenase type 1 expression and activity in cultured preadipocytes.  Endocrinology. 2007;  148 5268-5277
• 15 Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease.  Circ Res. 2005;  96 939-949
• 16 Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway.  Circulation. 2000;  102 1296-1301
• 17 Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada M, Hotta K, Nishida M, Takahashi M, Nakamura T, Shimomura I, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell.  Circulation. 2002;  105 2893-2898
• 18 Menzaghi C, Trischitta V, Doria A. Genetic influences of adiponectin on insulin resistance, type 2 diabetes, and cardiovascular disease.  Diabetes. 2007;  56 1198-1209
• 19 Garaulet M, Hernández-Morante JJ, Heredia FP de, Tébar FJ. Adiponectin, the controversial hormone.  Public Health Nutr. 2007;  10 1145-1150
• 20 Kunishima C, Inoue I, Oikawa T, Nakajima H, Komoda T, Katayama S. Activating effect of benzbromarone, a uricosuric drug, on peroxisome proliferator-activated receptors.  PPAR Res. 2007;  2007 36092
• 21 Liu QY, Quinet E, Nambi P. Adipocyte fatty acid-binding protein (aP2), a newly identified LXR target gene, is induced by LXR agonists in human THP-1 cells.  Mol Cell Biochem. 2007;  302 203-213
• 22 Han J, Hajjar DP, Zhou X, Gotto  Jr  AM, Nicholson AC. Oxidized low density lipoprotein decreases macrophage expression of scavenger receptor B-I.  J Biol Chem. 2001;  276 16567-16572
• 23 Takamura T, Nohara E, Nagai Y, Kobayashi K. Stage-specific effects of a thiazolidinedione on proliferation, differentiation and PPARgamma mRNA expression in 3T3-L1 adipocytes.  Eur J Pharmacol. 2001;  422 23-29
• 24 Hiuge A, Tenenbaum A, Maeda N, Benderly M, Kumada M, Fisman EZ, Tanne D, Matas Z, Hibuse T, Fujita K, Nishizawa H, Adler Y, Motro M, Kihara S, Shimomura I, Behar S, Funahashi T. Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level.  Arterioscler Thromb Vasc Biol. 2007;  27 635-641

Correspondence