Yoshida Hiroki, Tsuhako Rika, Atsumi Toshiyuki, Narumi Keiko, Watanabe Wataru, Sugita Chihiro, Kurokawa Masahiko
Department of Biochemistry, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
Department of Pharmacognosy, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
J Nat Med. 2017 Apr;71(2):442-448. doi: 10.1007/s11418-016-1063-4. Epub 2016 Dec 3.
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.
吡格列酮是一种过氧化物酶体增殖物激活受体γ（PPARγ）的完全激动剂，可用于治疗2型糖尿病。柚皮素是一种具有抗炎作用的柑橘类黄酮，已被证明可预防肥胖相关疾病并激活PPARγ。本研究的目的是调查饮食中的柚皮素是否会影响吡格列酮的作用。我们给津村铃木肥胖糖尿病（TSOD）小鼠连续4周灌胃柚皮素（100mg/kg）和吡格列酮（10mg/kg），然后进行口服葡萄糖耐量试验。我们发现，口服柚皮素减弱了吡格列酮在TSOD小鼠中的降血糖作用。然而，在给药期间，吡格列酮和柚皮素对空腹血糖水平、附睾脂肪垫重量和体重变化没有影响。吡格列酮抑制了TSOD小鼠脂肪组织中与肥胖相关的脂肪因子如金属蛋白酶组织抑制剂-1的表达，但这种作用被柚皮素减弱。然而，柚皮素对单次或重复给药后吡格列酮的药代动力学没有影响。在时间分辨荧光共振能量转移试验中，柚皮素表现出较弱的部分激动剂活性，但柚皮素干扰了吡格列酮的激动作用，这与部分激动作用一致。我们的结果表明，应避免联合使用柚皮素和吡格列酮。
