Genetic Study on the Effect of the Antidiabetic Drug ( Sitagliptin) on DNA and Chromosomes of Human Lymphocyte Culture

Abstract

AbstractBackground: Diabetes mellitus is a worsening worldwide health problem. It constitutes a major global health concern. Sitagliptin selectively inhibits dipeptidyl peptidase-4 (DPP-4) to manage type 2 diabetes mellitus (T2DM). It regulates the blood glucose level without risk of hypoglycemia or increase in body weight. In our study we investigated the effects of Sitagliptin on DNA and chromosomes in cultured human lymphocytes. Aim: To assess the genotoxic and cytotoxic effects of different concentrations of Sitagliptin on cultured human lymphocytes.Material and methods: Cultures were divided into 6 groups: control, positive control (Cisplatin) at concentration of 10 μg/mL and 4 different concentrations of Sitagliptin (125,250,500,1000 μg/mL). Sitagliptin genotoxicity and cytotoxicity were determined by using chromosomal aberrations (CAs), mitotic index (MI), comet assay and nucleic acids electrophoresis.Results: There was high significant increase in total chromosomal aberrations (TCAs) at 500, 1000 μg/mL of Sitagliptin compared to control. Other studied concentrations of Sitagliptin exhibited an increase in TCAs without significant relation. Compared to control, there was a significant increase in mitotic index at 125 μg/mL of Sitagliptin but non-significant increase at 250 μg/mL of Sitagliptin. However, at 500, 1000 μg/mL of Sitagliptin, there was a significant decrease in MI. Regarding comet assay, there was significant and high significant increase in total DNA damage at 500,1000 μg/mL of Sitagliptin respectively. Nucleic acids electrophoresis not digested with RNase showed that optical density value of RNA was maximum at 125 μg/mL then gradually decreased till reach the minimum level at 1000 μg/mL of Sitagliptin indicating its toxicity. Genomic DNA fragmentation results indicated that Sitagliptin caused a slight damage of DNA in the form of necrosis in a concentration dependent manner. Conclusion: Sitagliptin induces significant genotoxic and cytotoxic effects on the cultured human lymphocytes at concentrations of (500, 1000 μg/mL).