Sliwinska Agnieszka, Blasiak Janusz, Kasznicki Jacek, Drzewoski Jozef
Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, Zgierz, Poland.
Chem Biol Interact. 2008 Jun 17;173(3):159-65. doi: 10.1016/j.cbi.2008.03.017. Epub 2008 Apr 8.
Type 2 diabetes mellitus is associated with elevated level of oxidative stress, which is one of the most important factors responsible for the development of chronic complications of this disease. Moreover, it was shown that diabetic patients had increased level of oxidative DNA damage and decreased effectiveness of DNA repair. These changes may be associated with increased risk of cancer in T2DM patients, since DNA damage and DNA repair play a pivotal role in malignant transformation. It was found that gliclazide, an oral hypoglycemic drug with antioxidant properties, diminished DNA damage induced by free radicals. Therefore, the aim of the present study was to evaluate the in vitro impact of gliclazide on: (i) endogenous basal and oxidative DNA damage, (ii) DNA damage induced by hydrogen peroxide and (iii) the efficacy of DNA repair of such damage. DNA damage and DNA repair in peripheral blood lymphocytes of 30 T2DM patients and 30 non-diabetic individuals were evaluated by alkaline single cell electrophoresis (comet) assay. The extent of oxidative DNA damage was assessed by DNA repair enzymes: endonuclease III and formamidopyrimidine-DNA glycosylase. The endogenous basal and oxidative DNA damages were higher in lymphocytes of T2DM patients compared to non-diabetic subjects and gliclazide decreased the level of such damage. The drug significantly decreased the level of DNA damage induced by hydrogen peroxide in both groups. Gliclazide increased the effectiveness of DNA repair in lymphocytes of T2DM patients (93.4% (with gliclazide) vs 79.9% (without gliclazide); P< or =0.001) and non-diabetic subjects (95.1% (with gliclazide) vs 90.5% (without gliclazide); P< or =0.001). These results suggest that gliclazide may protect against the oxidative stress-related chronic diabetes complications, including cancer, by decreasing the level of DNA damage induced by reactive oxygen species.
2型糖尿病与氧化应激水平升高相关，氧化应激是该疾病慢性并发症发生的最重要因素之一。此外，研究表明糖尿病患者的氧化DNA损伤水平升高，DNA修复效率降低。这些变化可能与2型糖尿病患者患癌风险增加有关，因为DNA损伤和DNA修复在恶性转化中起关键作用。研究发现，具有抗氧化特性的口服降糖药格列齐特可减少自由基诱导的DNA损伤。因此，本研究的目的是评估格列齐特在体外对以下方面的影响：（i）内源性基础和氧化DNA损伤；（ii）过氧化氢诱导的DNA损伤；（iii）此类损伤的DNA修复效率。通过碱性单细胞电泳（彗星）试验评估30例2型糖尿病患者和30例非糖尿病个体外周血淋巴细胞中的DNA损伤和DNA修复情况。通过DNA修复酶：内切酶III和甲酰胺嘧啶-DNA糖基化酶评估氧化DNA损伤的程度。与非糖尿病受试者相比，2型糖尿病患者淋巴细胞中的内源性基础和氧化DNA损伤更高，而格列齐特可降低此类损伤的水平。该药物在两组中均显著降低了过氧化氢诱导的DNA损伤水平。格列齐特提高了2型糖尿病患者淋巴细胞（使用格列齐特时为93.4%，未使用时为79.9%；P≤0.001）和非糖尿病受试者（使用格列齐特时为95.1%，未使用时为90.5%；P≤0.001）的DNA修复效率。这些结果表明，格列齐特可能通过降低活性氧诱导的DNA损伤水平，预防与氧化应激相关的慢性糖尿病并发症，包括癌症。
