Department of Molecular Biology, Faculty of Arts and Sciences, Division of Biology, Marmara University, Istanbul, Turkey.
Department of Medical Services and Techniques, Istanbul University Cerrahpasa, Istanbul, Turkey.
Curr Drug Saf. 2021;16(3):252-258. doi: 10.2174/1574886315666210106141936.
Clopidogrel has been commonly prescribed as a selective P2Y12 receptor antagonist to reduce heart attack and stroke risk. Nearly 10% of absorbed clopidogrel is metabolized to active forms by cytochrome P450 (CYP) enzymes in the liver and 90% to inactive clopidogrel carboxylate by esterases.
Since different forms of clopidogrel have cytotoxic potential, our aim was to determine the effect of 7.5, 40, and 75μM clopidogrel over DNA damage in adipocytes and hepatocytes.
In the present study, DNA damage was investigated by Comet analysis using 3T3-L1 adipocytes and Alpha Mouse 12 (AML-12) hepatocytes.
DNA fragmentation was found to be increased as a response to 7.5 μM, 40 μM, and 75 μM clopidogrel treatment compared to non-treated control groups in AML-12 hepatocytes (p<0.01, p<0.001, p<0.01 respectively) and 3T3-L1 adipocytes (p<0.001, p<0.001 and p<0.001respectively). DNA damage levels as a response to clopidogrel treatment were found to be higher in 3T3-L1 adipocytes than AML-12 hepatocytes. Also, DNA damage levels in adipocytes and hepatocytes were found to increase dose-dependently for 7.5 and 40 μM clopidogrel, whereas decreased as a response to 75 μM.
According to our results, clopidogrel results in more DNA damage in adipocytes than in hepatocytes. The molecular mechanism of clopidogrel genotoxicity needs to be further investigated especially in adipose tissue.
氯吡格雷作为一种选择性 P2Y12 受体拮抗剂被广泛用于降低心脏病发作和中风的风险。吸收的氯吡格雷近 10%被肝脏中的细胞色素 P450（CYP）酶代谢为活性形式，90%转化为无活性的氯吡格雷羧酸酯。
由于氯吡格雷的不同形式具有细胞毒性潜力，我们的目的是确定 7.5、40 和 75μM 氯吡格雷对脂肪细胞和肝细胞中 DNA 损伤的影响。
在本研究中，使用 3T3-L1 脂肪细胞和 Alpha Mouse 12（AML-12）肝细胞通过彗星分析研究 DNA 损伤。
与未处理的对照组相比，AML-12 肝细胞（p<0.01，p<0.001，p<0.01）和 3T3-L1 脂肪细胞（p<0.001，p<0.001 和 p<0.001）中，7.5μM、40μM 和 75μM 氯吡格雷处理均导致 DNA 片段化增加。在 3T3-L1 脂肪细胞中，氯吡格雷处理引起的 DNA 损伤水平高于 AML-12 肝细胞。此外，7.5 和 40μM 氯吡格雷的剂量依赖性增加导致脂肪细胞和肝细胞中的 DNA 损伤水平增加，而 75μM 则减少。
根据我们的结果，氯吡格雷在脂肪细胞中引起的 DNA 损伤比在肝细胞中更多。氯吡格雷遗传毒性的分子机制需要进一步研究，特别是在脂肪组织中。
