Trancriptional profiling of rat bladder after daily administration of Pioglitazone and Rosiglitazone in vivo (miRNA)

The purpose of the study was to investigate the nongenotoxic carcinogenic effect of Pioglitazone. Pioglitazone is a PPARgamma agonist and is known to cause bladder tumours in male rats and an increase in the incidence of bladder cancer in humans has been observed in patients treated with Pioglitazone. Pioglitazone is not considered genotoxic or carcinogenic in mice and tumours are only observed in male rats suggesting a nongenotoxic mechanism of tumorigenesis. A suggested hypothesis is urinary calculi formation and subsequent irritation, hyperplasia and metaplasia. Rosiglitazone was used as reference compound as this PPARgamma agonist does not cause changes in the bladder but cause lipoma/liposarcoma in rats.本研究旨在探讨吡格列酮（Pioglitazone）的无遗传毒性致癌活性。吡格列酮是过氧化物酶体增殖物激活受体γ（PPARgamma）激动剂，已知可诱发雄性大鼠膀胱肿瘤；临床观察显示，接受吡格列酮治疗的患者膀胱癌发病率有所升高。吡格列酮在小鼠体内未被认定具有遗传毒性或致癌性，仅在雄性大鼠中观察到肿瘤，这提示其肿瘤发生机制属于非遗传毒性途径。目前提出的假说为尿路结石形成后引发尿路刺激、增生与化生。罗格列酮（Rosiglitazone）被用作参比化合物，该过氧化物酶体增殖物激活受体γ激动剂不会引发膀胱病变，但可诱发大鼠脂肪瘤/脂肪肉瘤。