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

DISCUSSION

The study provides valuable insights into the interaction of clopidogrel and its metabolite, 2-oxoclopidogrel, with the enzyme AKR1D1. The enzymatic assays demonstrate that neither clopidogrel nor its metabolite, 2-oxoclopidogrel, acts as a substrate or inhibitor of AKR1D1. This aligns with the known specificity of AKR1D1, which predominantly interacts with steroidal compounds and not with non-ste- roidal drugs like clopidogrel. The absence of inhibition is significant because it suggests that clopidogrel does not interfere with AKR1D1’s essential role in bile acid synthesis and steroid hormone clearance, thus preserving critical metabolic processes (17, 18, 20, 30). Disruption of this processes could impair digestion, absorption, and drug solubilization, which further emphasizes the physiological importance of AKR1D1’s functional integrity. While AKR1D1’s substrate specificity appears to favor steroidal compounds, its structural homology with AKR1C enzymes - which can interact with both steroi- dal and non-steroidal substrates - raises the possibility that AKR1D1 could be flexible under certain conditions (19, 30, 31). Although studies have demonstrated that certain non-steroidal compounds, including indometha- cin, mefenamic acid, and 4-benzoylbenzoic acid, which are potent inhibitors of AKR1C enzymes, do not inhibit AKR1D1 (31), only three non-steroidal compounds have been evaluated to date. Given the limited scope of these investigations, the possibility remains that AKR1D1 could interact with other non-steroidal substrates or inhibitors, warranting further exploration. The potential flexibility in AKR1D1’s substrate speci- ficity is an intriguing aspect of the enzyme’s functional- ity, particularly when considered in the context of genetic polymorphisms, such as the AKR1D1*36 variant that has been is associated with an increased risk of major adverse cardiovascular and cerebrovascular events (MACCE) in pa- tients treated with clopidogrel (22). While the AKR1D1*36 polymorphism has been linked to altered expression levels and downstream effects on CYP enzyme regulation (21), its direct impact on enzymatic function and substrate specific- ity remains unexplored. By contrast, engineered mutations, such as the E120H substitution, have demonstrated that sin- gle amino acid changes can significantly alter AKR1D1’s enzymatic activity and substrate specificity (32). These findings highlight the potential for naturally occurring genetic variants, like AKR1D1*36, to similarly influence enzyme functionality, warranting further investigation. Gene expression analyses further demonstrated that clopidogrel and 2-oxoclopidogrel do not modulate AKR1D1 expression at the transcriptional level. This find- ing implies that clopidogrel does not interfere with the production of 5β-reduced steroids, metabolic products of AKR1D1 that regulate CYP enzyme expression via nuclear receptor pathways such as FXR, CAR, and PXR (21). Consequently, the lack of AKR1D1 modulation by clopidogrel reduces the likelihood of indirect effects on CYP enzyme activity, which could otherwise alter the metabolism of co-administered drugs. This study’s findings should be interpreted with cau- tion regarding clinical relevance. In vivo systems involve a complex interplay of metabolic factors that may not be fully represented in the in vitro model used here. Therefore, further research is necessary to validate these observations and assess the broader implications of AKR1D1 and its genetic variations on drug metabolism as well as their potential impact on clinical outcomes particularly in the context of personalized medicine.

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