Investigation of genotoxicity of dapagliflozin in drosophila melanogaster using COMET, SMART and behavioral tests

This study aimed to investigate the possible genotoxic and cytotoxic effects of Dapagliflozin (DAPA), a sodium glucose cotransporter inhibitor used in the treatment of type 2 diabetes mellitus (T2DM), on Drosophila melanogaster due to the concern raised by liver damage as well as bladder and breast cancer cases reported due to drug use in clinical studies. DAPA is on the United States Food and Drug Administration watch list and is a drug on the additional watch list in our country. Although breast and bladder cancer cases have been reported due to dapagliflozin use, no cancer findings have been found in animal experiments. However, due to the lack of information about its potential effects on humans, it is very important to conduct genotoxic evaluations of DAPA and to reconsider its use as a result of these evaluations. This study investigated the behavioral toxicity of four different concentrations of DAPA, 0.1, 1, 5 and 10 mM, on D. melanogaster and DNA damage detection with the Comet assay. In addition, the genotoxic potential of DAPA with three different concentrations determined as 0.225, 0.45 and 0.9 mM was evaluated with the Drosophila Smart test. According to the results of the behavioral toxicity experiments, a decrease in larval weight was detected compared to the control group and this decrease at doses of 1, 5 and 10 mM was found to be statistically significant. In the results of the larval crawling and negative geotaxis experiments, the decreases in the last dose of 10 mM were found to be statistically significant. While the changes in the exit success in the 5 and 10 mM application groups were found to be statistically significant, the changes in the pupa formation success, pupal position and adult weight experiments were not statistically significant when compared to the control group. In the results of the Comet test performed on D. melanogaster, the changes compared to the control group values were found to be significant in all application groups. In the smart test system, only the frequency increases in the last dose of 0.9 mM, out of the 0.225, 0.45 and 0.9 mM application doses, are statistically significant. DAPA, which has a widespread use, was removed from the market once in previous years for reliability reasons and then re-entered the market, which reveals the need for this pharmaceutical agent to be evaluated with different test systems in order to reveal its different effects. The fact that the data obtained with these test systems related to DAPA have been brought to the literature for the first time increases the importance of this study and has the nature of a fundamental study.