The Association between Pon 1 and Clopidogrel Responsiveness

The discovery of Clopidogrel, one of the most widely used anti-platelet drugs, is perhaps the most important discovery made after aspirin in reducing the risk of platelet aggregation and blood clotting. Throughout the years, it has shown to be effective in preventing blood clot formation in coronary arteries, as well as ischemic events in the brain and in the peripheries.  

Clopidogrel responsiveness-

An important feature in patients taking Clopidogrel is its inconsistent action depending on the person’s ability to metabolize the drug into its active ingredients. In instances where Clopidogrel does not function effectively, it has been observed that the risk of developing stent thrombosis in case of percutaneous coronary interventions (PCI) and the development of myocardial infarctions in coronary artery disease is significantly high.

Thus, researchers worldwide were trying hard to explain this phenomenon, which eluded the scientific community for several decades. However, with the advent of advance genetic research, it was possible to shed light into a genetic basis for this variable responsiveness.

Evidence for genetic contribution towards inconsistent Clopidogrel response-

According to researchers, there are several enzymes, which contributes towards the metabolism of Clopidogrel and among them, one of the earliest discoveries was the cytochrome P450 2C19 (CYP2C19) gene. It plays an important role in producing the cytochrome P450 isozyme which converts Clopidogrel into one of its active metabolites. Studies such as the genome-wide association study of an Amish population have linked the variations in CYP2C19 gene with variable responses shown in platelet function among those who use Clopidogrel therapy.

However, in a recent study, researchers from Netherlands have uncovered another enzyme named as the paraoxonase-1 (PON-1) enzyme, which also contributes towards the metabolism of Clopidogrel. According to these researchers, PON-1 variations have also contributed towards the Clopidogrel response variability while they consider the effects of PON-1 to be more significant than the effects of CYP2C19 towards the same.

Loopholes in studies leading to significant PON-1 influence over CYP2C19 activity-

Although the findings of PON-1 and its effects over platelet activity remains to be important, there are certain gray areas which needs further scientific evidence to substantiate. One such instance is the inability to explain why the PON-1 gene region did not highlight as influential in earlier studies such as the genome-wide association study of an Amish population. The second instance is the exclusion of how CYP2C19 influenced the study results in which PON-1 was highlighted as the major contributor towards the variable response of Clopidogrel.

Contradictory findings regarding PON-1 and CYP2C19 influence on Clopidogrel response-

In a study published in the European Heart Journal, the researchers have concluded that, while PON-1 Q192R genotype did not influence the platelet response among those patients who are using Clopidogrel, the presence of CYP2C19 did have a significant impact on the antiplatelet effect and towards the risk of coronary stent thrombosis.


Although contradictory research evidence mounts in relation to the efficacy of the treatment with Clopidogrel, the place of its use in managing patients with potential vascular diseases remains to be significant. Therefore, the answer to the question ‘who will receive its expected benefits’ remain unresolved and still un-substantiated.