Balkan Journal of Medical Genetics

IN VITRO ANALYSIS OF AKR1D1 INTERACTIONS WITH CLOPIDOGREL: EFFECTS ON ENZYME ACTIVITY AND GENE EXPRESSION
Shutevska K1*, Kadifkova Panovska T1, Zhivikj Z1, Kapedanovska Nestorovska A2
*Corresponding Author: *Corresponding Author: Kristina Shutevska, Majka Tereza 47, 1000 Skopje, Republic of North Macedonia, +389 2 1326032 (142), k.sutevska@ff.ukim.edu.mk
page: 69

INTRODUCTION

Clopidogrel, a P2Y12 receptor antagonist, is a cor- nerstone of dual antiplatelet therapy alongside aspirin, widely used to prevent major cardiovascular events in patients with acute coronary syndromes or undergoing percutaneous coronary interventions (1, 2). While clopi- dogrel has been shown to be more effective than aspirin in reducing the risks of myocardial infarction, ischemic stroke, and vascular death, there remains significant vari- ability in treatment outcomes among patients (3, 4). This variability can range from reduced efficacy or resistance to therapy, affecting 5–44% of patients, to increased risk of bleeding due to excessive antiplatelet activity (5, 6). The phenomenon of “clopidogrel resistance” presents a major clinical challenge, particularly because the underly- ing mechanisms are not fully understood (7–9). The metabolism of clopidogrel is complex. As a prod- rug, it undergoes two primary processes: hydrolysis by carboxylesterase 1 (CES1), which inactivates the majority of the drug, and a two-step activation mediated by several cytochrome P450 (CYP) enzymes, which convert clopi- dogrel to its active form (10, 11). Among these, CYP2C19 is the most crucial, with polymorphisms in this enzyme (CYP2C19*2, *3, and *17) being major determinants of clopidogrel’s variable pharmacokinetics and treatment out- comes (12–14). However, these genetic variations explain only about 12% of the observed variability, leaving much of the interindividual differences unexplained (12, 15). The variability in CYP enzyme activity and its ef- fects on drug metabolism extend beyond clopidogrel, as CYP enzymes play a pivotal role in the biotransfor- mation of many medications (16). Aldo-Keto Reductase 1D1 (AKR1D1), an enzyme critical in bile acid synthe- sis and steroid clearance (17–19), has been identified by Chaudhry et al. (2013) as a key trans-regulator of the CYP enzyme network, suggesting a broader regulatory mechanism. AKR1D1 regulates CYP2C19, CYP3A4, and CYP2C9 expression via its metabolic products. Specifical- ly, the 5β-reduced steroids generated by AKR1D1 activity act as ligands for nuclear receptors such as farnesoid X receptor (FXR), pregnane X receptor (PXR), and consti- tutive androstane receptor (CAR), which in turn regulate CYP enzyme expression (20, 21). The AKR1D1*36 poly- morphism (rs1872930), in particular, leads to increased expression of AKR1D1, resulting in the upregulation of these CYP enzymes (21). Kapedanovska et al. (2019) explored this hypothesis in the context of clopidogrel and demonstrated that the AKR1D1*36 allele is associated with an increased risk of major adverse cardiovascular and cerebrovascular events (MACCE) in patients treated with clopidogrel, establishing AKR1D1 as an independent risk factor (22). Building on previous findings linking AKR1D1*36 to the regulation of the cytochrome P450 enzyme network, this study seeks to elucidate the potential role of AKR1D1 in clopidogrel metabolism. Specifically, the research aims to evaluate whether clopidogrel and its inactive metabo- lite, 2-oxoclopidogrel, act as substrates or inhibitors of the AKR1D1 enzyme, thereby elucidating potential in- teractions at the protein level. Furthermore, the study in- vestigates the influence of clopidogrel and its metabolite on AKR1D1 gene expression in HepG2 cells to explore potential mechanisms that could modulate clopidogrel metabolism. These investigations are intended to provide a deeper understanding of AKR1D1’s involvement in drug metabolism and its broader implications for pharmacologi- cal research.

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