GENETIC POLYMORPHISMS OF CYP2C9 GENE AMONG VOLUNTARY DONORS FROM THE MACEDONIAN BONE MARROW DONOR REGISTRY AND ITS IMPLICATIONS ON THERAPEUTIC DOSAGE OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
Keywords:
pharmacogenetics, CYP2C9 gene, NSAIDsAbstract
The CYP2C9 gene is related to the metabolism of several non-steroidal anti-inflammatory drugs (NSAID). Presence of different allele polymorphisms is associated with lack of enzyme activity and can lead to therapeutic failure. The aim of our study was to provide data about the distribution of CYP2C9 alleles in voluntary donors from the Macedonian Bone Marrow Donor Registry (MBMDR) and to calculate the activation score (AS) of CYP2C9 enzyme.
We analyzed samples of 25 voluntary bone marrow donors by multiplex real-time polymerase chain reaction (PCR) test for detection of CYP2C9*2 and *3 polymorphisms. The samples were analyzed with 7500 Real-Time PCR System with FAM, VIC, ROX and Cy5 filters.
We identified 13 donors with *1*1 diplotype, 7 with *1*3 diplotype, 4 with *1*2 diplotype and 1 donor with *2*3 diplotype. According to the calculated AS, 13 out of 25 individuals (54%) had normal AS value of 2, which refers to normal metabolizers (NMs). Eleven donors (44%) had AS value of 1-1.5, which refers to intermediate metabolizers (IMs) and only one donor (4%) had AS value of 0.5 which refers to poor metabolizer (PM).
Even though the number of donors in our study is small and the results need to be evaluated in a larger cohort, it shows that different genotypes in the CYP2C9 gene are present among donors from MBMR. It is important to have it in mind especially when using NSAIDs that can be bought over-the-counter.
References
Makia NL, Surapureddi S, Monostory K, Prough RA, Goldstein JA. Regulation of human CYP2C9 expression by electrophilic stress involves activator protein 1 activation and DNA looping. Mol Pharmacol 2014; 86(2): 125-137. doi: 10.1124/mol.114.092585.
https://www.ncbi.nlm.nih.gov/gene/1559#genomic-regions-transcripts-products, Accessed on September 2022.
Dean L, Kane M. Celecoxib Therapy and CYP2C9 Genotype. 2016 Aug 18 [Updated 2021 Jan 25]. In: Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012.
Theken KN, Lee CR, Gong L, Caudle KE, Formea CM, Gaedigk A, et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clin Pharmacol Ther 2020; 108(2): 191-200. doi: 10.1002/cpt.1830.
Celinšćak Ž, Zajc Petranović M, Šetinc M, Stojanović Marković A, Peričić Salihović M, Marija Zeljko H, et al. Pharmacogenetic distinction of the Croatian population from the European average. Croat Med J 2022; 30; 63(2): 117-125. doi: 10.3325/cmj.2022.63.117.
https://www.pharmgkb.org/vip/PA166169913 Accessed on September 2022.
Schleiff MA, Crosby S, Blue M, Schleiff BM, Boysen G, Miller GP. CYP2C9 and 3A4 play opposing roles in bioactivation and detoxification of diphenylamine NSAIDs. Biochem Pharmacol 2021; 194: 114824. doi: 10.1016/j.bcp.2021.114824.
Davis A, Robson J. The dangers of NSAIDs: look both ways. Br J Gen Pract 2016; 66(645): 172-173. doi: 10.3399/bjgp16X684433.
López-Rodríguez R, Novalbos J, Gallego-Sandín S, Román-Martínez M, Torrado J, Gisbert JP, et al. Influence of CYP2C8 and CYP2C9 polymorphisms on pharmacokinetic and pharmacodynamic parameters of racemic and enantiomeric forms of ibuprofen in healthy volunteers. Pharmacol Res 2008; 58(1): 77-84. doi: 10.1016/j.phrs.2008.07.004.
Jakovski K, Nestorovska AK, Labacevski N, Dimovski AJ. Characterization of the most common CYP2C9 and CYP2C19 allelic variants in the population from the Republic of Macedonia. Pharmazie 2013; 68(11): 893-898.
Vidović S, Škrbić R, Stojiljković MP, Vidović V, Bećarević J, Stoisavljević-Šatara S, et al. Prevalence of five pharmacologically most important CYP2C9 and CYP2C19 allelic variants in the population from the Republic of Srpska in Bosnia and Herzegovina. Arh Hig Rada Toksikol 2021; 28; 72(3): 129-134. doi: 10.2478/aiht-2021-72-3499.
Ganoci L, Božina T, Mirošević Skvrce N, Lovrić M, Mas P, Božina N. Genetic polymorphisms of cytochrome P450 enzymes: CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in the Croatian population. Drug Metab Pers Ther. 2017;32(1):11-21. doi: 10.1515/dmpt-2016-0024.
Arvanitidis K, Ragia G, Iordanidou M, Kyriaki S, Xanthi A, Tavridou A, et al. Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population. Fundam Clin Pharmacol 2007; 21(4): 419-426. doi: 10.1111/j.1472-8206.2007.00510.x.
