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Journal of Natural Medicines

, Volume 71, Issue 2, pp 442–448 | Cite as

Naringenin interferes with the anti-diabetic actions of pioglitazone via pharmacodynamic interactions

  • Hiroki YoshidaEmail author
  • Rika Tsuhako
  • Toshiyuki Atsumi
  • Keiko Narumi
  • Wataru Watanabe
  • Chihiro Sugita
  • Masahiko Kurokawa
Note

Abstract

Pioglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) full agonist and useful for the treatment of type 2 diabetes mellitus. Naringenin is a citrus flavonoid with anti-inflammatory actions, which has been shown to prevent obesity-related diseases and to activate PPARγ. The aim of this study was to investigate whether dietary naringenin affects the actions of pioglitazone. We administered naringenin (100 mg/kg) and pioglitazone (10 mg/kg) to Tsumura Suzuki Obese Diabetes (TSOD) mice for 4 weeks and then conducted an oral glucose tolerance test. We found that oral administration of naringenin attenuated the hypoglycemic action of pioglitazone in TSOD mice. However, pioglitazone and naringenin did not affect fasting blood glucose levels, epididymal fat pad weight and body weight changes in this administration period. Pioglitazone suppressed expression of obesity-related adipokines such as tissue inhibitor of metalloproteinases-1 in adipose tissue of TSOD mice, but this effect was attenuated by naringenin. However, naringenin did not affect the pharmacokinetics of pioglitazone after single or repeated administration. Naringenin exhibited weak partial agonist activity in time-resolved fluorescence resonance energy transfer assay, but naringenin interfered with pioglitazone agonism, consistent with partial agonism. Our results suggest that it is advisable to avoid administering a combination of naringenin and pioglitazone.

Keywords

Naringenin Pioglitazone PPARγ Food−drug interaction 

Notes

Acknowledgements

We are grateful to Ms. Yukiko Shimoda, Ms. Momoko Kawano, and Ms. Chiaki Shin. (Kyushu University of Health and Welfare) for their kind support and helpful suggestions. This work was supported in part by a Grant-in-Aid for Scientific Research (Grant Nos. 24790182 and 15K18949 to H. Yoshida) from the Japan Society for the Promotion of Science.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Berger J, Moller DE (2002) The mechanisms of action of PPARs. Annu Rev Med 53:409–435CrossRefPubMedGoogle Scholar
  2. 2.
    Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM (1994) mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8:1224–1234CrossRefPubMedGoogle Scholar
  3. 3.
    Lehrke M, Lazar MA (2005) The many faces of PPARgamma. Cell 123:993–999CrossRefPubMedGoogle Scholar
  4. 4.
    Ricote M, Glass CK (2007) PPARs and molecular mechanisms of transrepression. Biochim Biophys Acta 1771:926–935CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C, Blazevic T, Schwaiger S, Rollinger JM, Heiss EH, Schuster D, Kopp B, Bauer R, Stuppner H, Dirsch VM, Atanasov AG (2014) Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARgamma): a review. Biochem Pharmacol 92:73–89CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Higgins LS, Depaoli AM (2010) Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulation as a strategy for safer therapeutic PPARgamma activation. Am J Clin Nutr 91:267S–272SCrossRefPubMedGoogle Scholar
  7. 7.
    van Acker FA, Schouten O, Haenen GR, van der Vijgh WJ, Bast A (2000) Flavonoids can replace alpha-tocopherol as an antioxidant. FEBS Lett 473:145–148CrossRefPubMedGoogle Scholar
  8. 8.
    Lin HY, Shen SC, Chen YC (2005) Anti-inflammatory effect of heme oxygenase 1: glycosylation and nitric oxide inhibition in macrophages. J Cell Physiol 202:579–590CrossRefPubMedGoogle Scholar
  9. 9.
    So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK (1996) Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer 26:167–181CrossRefPubMedGoogle Scholar
  10. 10.
    Knekt P, Kumpulainen J, Jarvinen R, Rissanen H, Heliovaara M, Reunanen A, Hakulinen T, Aromaa A (2002) Flavonoid intake and risk of chronic diseases. Am J Clin Nutr 76:560–568PubMedGoogle Scholar
  11. 11.
    Mulvihill EE, Allister EM, Sutherland BG, Telford DE, Sawyez CG, Edwards JY, Markle JM, Hegele RA, Huff MW (2009) Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes 58:2198–2210CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kannappan S, Anuradha CV (2010) Naringenin enhances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome. Eur J Nutr 49:101–109CrossRefPubMedGoogle Scholar
  13. 13.
    Yoshida H, Takamura N, Shuto T, Ogata K, Tokunaga J, Kawai K, Kai H (2010) The citrus flavonoids hesperetin and naringenin block the lipolytic actions of TNF-alpha in mouse adipocytes. Biochem Biophys Res Commun 394:728–732CrossRefPubMedGoogle Scholar
  14. 14.
    Yoshida H, Watanabe W, Oomagari H, Tsuruta E, Shida M, Kurokawa M (2013) Citrus flavonoid naringenin inhibits TLR2 expression in adipocytes. J Nutr Biochem 24:1276–1284CrossRefPubMedGoogle Scholar
  15. 15.
    Yoshida H, Watanabe H, Ishida A, Watanabe W, Narumi K, Atsumi T, Sugita C, Kurokawa M (2014) Naringenin suppresses macrophage infiltration into adipose tissue in an early phase of high-fat diet-induced obesity. Biochem Biophys Res Commun 454:95–101CrossRefPubMedGoogle Scholar
  16. 16.
    Goldwasser J, Cohen PY, Yang E, Balaguer P, Yarmush ML, Nahmias Y (2010) Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: role of PPARalpha. PPARgamma and LXRalpha. PLoS One 5:e12399CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Liu L, Shan S, Zhang K, Ning ZQ, Lu XP, Cheng YY (2008) Naringenin and hesperetin, two flavonoids derived from Citrus aurantium up-regulate transcription of adiponectin. Phytother Res 22:1400–1403CrossRefPubMedGoogle Scholar
  18. 18.
    Yamashita K, Murakami H, Okuda T, Motohashi M (1996) High-performance liquid chromatographic determination of pioglitazone and its metabolites in human serum and urine. J Chromatogr B Biomed Appl 677:141–146CrossRefPubMedGoogle Scholar
  19. 19.
    Suzuki A, Yasuno T, Kojo H, Hirosumi J, Mutoh S, Notsu Y (2000) Alteration in expression profiles of a series of diabetes-related genes in db/db mice following treatment with thiazolidinediones. Jpn J Pharmacol 84:113–123CrossRefPubMedGoogle Scholar
  20. 20.
    Ishida H, Takizawa M, Ozawa S, Nakamichi Y, Yamaguchi S, Katsuta H, Tanaka T, Maruyama M, Katahira H, Yoshimoto K, Itagaki E, Nagamatsu S (2004) Pioglitazone improves insulin secretory capacity and prevents the loss of beta-cell mass in obese diabetic db/db mice: possible protection of beta cells from oxidative stress. Metab Clin Exp 53:488–494CrossRefPubMedGoogle Scholar
  21. 21.
    Kimura T, Kaneto H, Shimoda M, Hirukawa H, Okauchi S, Kohara K, Hamamoto S, Tawaramoto K, Hashiramoto M, Kaku K (2015) Protective effects of pioglitazone and/or liraglutide on pancreatic beta-cells in db/db mice: comparison of their effects between in an early and advanced stage of diabetes. Mol Cell Endocrinol 400:78–89CrossRefPubMedGoogle Scholar
  22. 22.
    Endo Y, Suzuki M, Yamada H, Horita S, Kunimi M, Yamazaki O, Shirai A, Nakamura M, Iso ON, Li Y, Hara M, Tsukamoto K, Moriyama N, Kudo A, Kawakami H, Yamauchi T, Kubota N, Kadowaki T, Kume H, Enomoto Y, Homma Y, Seki G, Fujita T (2011) Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARgamma-dependent nongenomic signaling. Cell Metab 13:550–561CrossRefPubMedGoogle Scholar
  23. 23.
    Karuppagounder V, Arumugam S, Thandavarayan RA, Pitchaimani V, Sreedhar R, Afrin R, Harima M, Suzuki H, Suzuki K, Nakamura M, Ueno K, Watanabe K (2015) Naringenin ameliorates daunorubicin induced nephrotoxicity by mitigating AT1R, ERK1/2-NFkappaB p65 mediated inflammation. Int Immunopharmacol 28:154–159CrossRefPubMedGoogle Scholar
  24. 24.
    Maquoi E, Munaut C, Colige A, Collen D, Lijnen HR (2002) Modulation of adipose tissue expression of murine matrix metalloproteinases and their tissue inhibitors with obesity. Diabetes 51:1093–1101CrossRefPubMedGoogle Scholar
  25. 25.
    Chavey C, Mari B, Monthouel MN, Bonnafous S, Anglard P, Van Obberghen E, Tartare-Deckert S (2003) Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. J Biol Chem 278:11888–11896CrossRefPubMedGoogle Scholar
  26. 26.
    Maury E, Ehala-Aleksejev K, Guiot Y, Detry R, Vandenhooft A, Brichard SM (2007) Adipokines oversecreted by omental adipose tissue in human obesity. Am J Physiol Endocrinol Metab 293:E656–E665CrossRefPubMedGoogle Scholar
  27. 27.
    Saglam F, Cavdar Z, Sarioglu S, Kolatan E, Oktay G, Yilmaz O, Camsari T (2012) Pioglitazone reduces peritoneal fibrosis via inhibition of TGF-beta, MMP-2, and MMP-9 in a model of encapsulating peritoneal sclerosis. Ren Fail 34:95–102CrossRefPubMedGoogle Scholar
  28. 28.
    Makino N, Sugano M, Satoh S, Oyama J, Maeda T (2006) Peroxisome proliferator-activated receptor-gamma ligands attenuate brain natriuretic peptide production and affect remodeling in cardiac fibroblasts in reoxygenation after hypoxia. Cell Biochem Biophys 44:65–71CrossRefPubMedGoogle Scholar
  29. 29.
    Zafiriou S, Stanners SR, Saad S, Polhill TS, Poronnik P, Pollock CA (2005) Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts. J Am Soc Nephrol 16:638–645CrossRefPubMedGoogle Scholar
  30. 30.
    Kawaguchi K, Sakaida I, Tsuchiya M, Omori K, Takami T, Okita K (2004) Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. Biochem Biophys Res Commun 315:187–195CrossRefPubMedGoogle Scholar
  31. 31.
    Meissburger B, Stachorski L, Roder E, Rudofsky G, Wolfrum C (2011) Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) controls adipogenesis in obesity in mice and in humans. Diabetologia 54:1468–1479CrossRefPubMedGoogle Scholar
  32. 32.
    Kanaze FI, Bounartzi MI, Georgarakis M, Niopas I (2007) Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects. Eur J Clin Nutr 61:472–477PubMedGoogle Scholar
  33. 33.
    Kulkarni AA, Woeller CF, Thatcher TH, Ramon S, Phipps RP, Sime PJ (2012) Emerging PPARgamma-independent role of PPARgamma ligands in lung diseases. PPAR Res 2012:705352CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Alam MA, Subhan N, Rahman MM, Uddin SJ, Reza HM, Sarker SD (2014) Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action. Adv Nutr 5:404–417CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan 2016

Authors and Affiliations

  1. 1.Department of Biochemistry, Graduate School of Clinical PharmacyKyushu University of Health and WelfareNobeokaJapan
  2. 2.Department of Pharmacognosy, Graduate School of Clinical PharmacyKyushu University of Health and WelfareNobeokaJapan
  3. 3.Department of Clinical Pharmacy, Graduate School of Clinical PharmacyKyushu University of Health and WelfareNobeokaJapan
  4. 4.Department of Microbiology, Graduate School of Clinical PharmacyKyushu University of Health and WelfareNobeokaJapan

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