DNA Damage in AML-12 Hepatocytes and 3T3-L1 Adipocytes Treated with Clopidogrel

Abstract

Background: 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. Objective: 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. Methods: In the present study, DNA damage was investigated by Comet analysis using 3T3-L1 adipocytes and Alpha Mouse 12 (AML-12) hepatocytes. Results: 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. Conclusion: 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.