Bedir Abdulkerim, Aliyazicioglu Yuksel, Bilgici Birsen, Yurdakul Zafer, Uysal Mehmet, Suvaci Duygu Erol, Okuyucu Ali, Kahraman Hakki, Hökelek Murat, Alvur Muhlise
Department of Biochemistry, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.
Environ Mol Mutagen. 2008 Apr;49(3):185-91. doi: 10.1002/em.20365.
Pioglitazone (PIO), a member of the thiazolidinedione class of antidiabetic agents, specifically targets insulin resistance. Drugs of this class act as ligands for the gamma subtype of the peroxisome proliferator-activated receptor. Although troglitazone, another drug in this class, displayed unacceptable hepatotoxicity, PIO was approved for human use by the U.S. Food and Drug Administration. To our knowledge, there are no published reports on the genotoxicity of PIO; however, the package insert indicates that it has minimal genotoxicity. In this study, we used the comet assay to investigate the DNA damage in the peripheral blood and liver cells of rats treated with PIO. Sixteen male Sprague-Dawley rats were randomly distributed into four groups, and dosed daily for 14 days by oral gavage with 0, 10, 20, and 40 mg/kg/day PIO. A dose-dependent increase in DNA damage, as assessed by % tail DNA, was observed in both hepatocytes and blood lymphocytes of the PIO-treated groups, with significant increases detected between the rats treated with all the doses of PIO and the control, and between the rats treated with different PIO doses (P < 0.005 to P < 0.0001). Treating nuclei from the exposed animals with an enzyme cocktail containing Fpg and Endonuclease III prior to performing the comet assay increased the level of DNA damage, which reflects oxidized purine and pyrimidine. Taken together, our data indicate that PIO is able to dose-dependently induce DNA damage in both the liver and blood lymphocytes of rats, which is partially due to the generation of oxidative lesions.
吡格列酮（PIO）是噻唑烷二酮类抗糖尿病药物的一种，专门针对胰岛素抵抗起作用。这类药物作为过氧化物酶体增殖物激活受体γ亚型的配体发挥作用。尽管该类中的另一种药物曲格列酮显示出不可接受的肝毒性，但PIO已被美国食品药品监督管理局批准用于人类。据我们所知，尚无关于PIO遗传毒性的公开报道；然而，药品说明书表明其具有最小的遗传毒性。在本研究中，我们使用彗星试验来研究用PIO处理的大鼠外周血和肝细胞中的DNA损伤。16只雄性Sprague-Dawley大鼠被随机分为四组，每天通过口服灌胃给予0、10、20和40mg/kg/天的PIO，持续14天。在PIO处理组的肝细胞和血液淋巴细胞中，均观察到以尾DNA百分比评估的DNA损伤呈剂量依赖性增加，在用所有剂量的PIO处理的大鼠与对照组之间以及用不同PIO剂量处理的大鼠之间检测到显著增加（P<0.005至P<0.0001）。在进行彗星试验之前，用含有Fpg和核酸内切酶III的酶混合物处理暴露动物的细胞核，增加了DNA损伤水平，这反映了氧化的嘌呤和嘧啶。综上所述，我们的数据表明PIO能够在大鼠的肝脏和血液淋巴细胞中剂量依赖性地诱导DNA损伤，这部分归因于氧化损伤的产生。
