Pediatric pharmacogenetics: profiling CYP2C8 polymorphisms at King Abdulaziz University Dental Clinic
-
Amina M. Bagher
,
Rania A. Aboud
Abstract
Objectives
Ibuprofen, a widely used non-steroidal anti-inflammatory (NSAID) for managing pain and inflammation in pediatric patients, is metabolized by the CYP2C8 enzyme. Studies suggest that the CYP2C8*2, *3, and *4 variations of the CYP2C8 gene diminish ibuprofen metabolism, increasing the risk of adverse reactions. The aim of this study was to determine the frequency of the CYP2C8*2, *3, and *4 alleles and genotypes in a pediatric population attending the King Abdulaziz University dental clinic and compare our findings to those of other populations.
Methods
A cross-sectional study was conducted with 140 healthy Saudi children ages 6–12. Saliva samples were collected using Oragene™ DNA Sample Collection Kits and analyzed for polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Results
The study identified that CYP2C8*2 AA, AT, and TT genotypes occurred at frequencies of 87.86 %, 9.29 %, and 2.86 %, respectively. For CYP2C8*3, AA, AG, and GG genotypes were found in 87.14 , 8.75, and 4.29 % of subjects, respectively. The CYP2C8*4 allele was less frequent, with CC and CG genotypes at 97.86 % and 2.14 %, respectively, and the GG genotype was absent. Allele frequencies for CYP2C8*2, *3, and *4 were 7.5 %, 8.57 %, and 1.07 %, respectively.
Conclusions
Our findings reveal that the allelic frequencies for the CYP2C8 polymorphisms in the Saudi pediatric cohort are substantially elevated compared to those reported in other Asian populations. This suggests Saudis may experience more varied drug responses, especially for medications that undergo metabolism by the CYP2C8 enzyme, like ibuprofen.
Acknowledgments
We want to thank all the patients who participated in the study.
-
Research ethics: The study protocol was revised and approved by the Research Ethics Committee at the King Abdulaziz University, Faculty of Dentistry (076-03-23).
-
Informed consent: Before enrollment, the participants and their parents/guardians signed Arabic informed consent forms.
-
Author contributions: The authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Use of Large Language Models, AI and Machine Learning Tools: None declared.
-
Conflict of interest: The authors state no conflict of interest.
-
Research funding: This project was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, Saudi Arabia, under Grant No G: 401-249-1440. The authors, therefore, acknowledge with thanks the DSR’s technical and financial support.
-
Data availability: Not applicable.
References
1. Nakajima, M, Fujiki, Y, Noda, K, Ohtsuka, H, Ohkuni, H, Kyo, S, et al.. Genetic polymorphisms of CYP2C8 in Japanese population. Drug Metab Dispos 2003;31:687–90. https://doi.org/10.1124/dmd.31.6.687.Search in Google Scholar PubMed
2. Ahmed, S, Zhou, Z, Zhou, J, Chen, S-Q. Pharmacogenomics of drug metabolizing enzymes and transporters: relevance to precision medicine. Dev Reprod Biol 2016;14:298–313. https://doi.org/10.1016/j.gpb.2016.03.008.Search in Google Scholar PubMed PubMed Central
3. McDonnell, AM, Dang, CH. Basic review of the cytochrome P450 system. J Adv Pract Oncol 2013;4:263–8. https://doi.org/10.6004/jadpro.2013.4.4.7.Search in Google Scholar PubMed PubMed Central
4. Shankar, K, Mehendale, HM. Cytochrome P450. In: Wexler, P, editor. Encyclopedia of toxicology, 3rd ed. Oxford: Academic Press; 2014:1125–7 pp.10.1016/B978-0-12-386454-3.00299-2Search in Google Scholar
5. Stavropoulou, E, Pircalabioru, GG, Bezirtzoglou, E. The role of cytochromes P450 in infection. Front Immunol 2018;9:89. https://doi.org/10.3389/fimmu.2018.00089.Search in Google Scholar PubMed PubMed Central
6. Dai, D, Zeldin, DC, Blaisdell, JA, Chanas, B, Coulter, SJ, Ghanayem, BI, et al.. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 2001;11:597–607. https://doi.org/10.1097/00008571-200110000-00006.Search in Google Scholar PubMed
7. Daily, EB, Aquilante, CL. Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies. Pharmacogenomics 2009;10:1489–510. https://doi.org/10.2217/pgs.09.82.Search in Google Scholar PubMed PubMed Central
8. Ogu, CC, Maxa, JL. Drug interactions due to cytochrome P450. SAVE Proc 2000;13:421–3. https://doi.org/10.1080/08998280.2000.11927719.Search in Google Scholar PubMed PubMed Central
9. Lynch, T, Price, A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007;76:391–6.Search in Google Scholar
10. Zanger, UM, Schwab, M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Therapeut 2013;138:103–41. https://doi.org/10.1016/j.pharmthera.2012.12.007.Search in Google Scholar PubMed
11. Zhou, Y, Ingelman-Sundberg, M, Lauschke, V. Worldwide distribution of cytochrome P450 alleles: a meta-analysis of population-scale sequencing projects. Clin Pharmacol Ther 2017;102:688–700. https://doi.org/10.1002/cpt.690.Search in Google Scholar PubMed PubMed Central
12. Bahadur, N, Leathart, JBS, Mutch, E, Steimel-Crespi, D, Dunn, SA, Gilissen, R, et al.. CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6alpha-hydroxylase activity in human liver microsomes. Biochem Pharmacol 2002;64:1579–89. https://doi.org/10.1016/s0006-2952(02)01354-0.Search in Google Scholar PubMed
13. Totah, R, Rettie, A. Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance. Clin Pharmacol Therapeut 2005;77:341–52. https://doi.org/10.1016/j.clpt.2004.12.267.Search in Google Scholar PubMed
14. Jiang, H, Sun, L, Huang, Z, Tan, X. Structural and functional insights into CYP2C8.3: a genetic polymorph of cytochrome P450 2C8. Sci China Chem 2010;53:2200–7. https://doi.org/10.1007/s11426-010-4087-8.Search in Google Scholar
15. Smith, HE, Jones, JP, Kalhorn, TF, Farin, FM, Stapleton, PL, Davis, CL, et al.. Role of cytochrome P450 2C8 and 2J2 genotypes in calcineurin inhibitor-induced chronic kidney disease. Pharmacogenetics Genom 2008;18:943–53. https://doi.org/10.1097/fpc.0b013e32830e1e16.Search in Google Scholar
16. Aquilante, CL, Niemi, M, Gong, L, Altman, RB, Klein, TE. PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 8. Pharmacogenetics Genom 2013;23:721–8. https://doi.org/10.1097/fpc.0b013e3283653b27.Search in Google Scholar PubMed PubMed Central
17. Paganotti, GM, Gallo, BC, Verra, F, Sirima, BS, Nebie, I, Diarra, A, et al.. Human genetic variation is associated with plasmodium falciparum drug resistance. J Infect Dis 2011;204:1772–8. https://doi.org/10.1093/infdis/jir629.Search in Google Scholar PubMed
18. Yu, L, Shi, D, Ma, L, Zhou, Q, Zeng, S. Influence of CYP2C8 polymorphisms on the hydroxylation metabolism of paclitaxel, repaglinide and ibuprofen enantiomers in vitro: EFFECT OF CYP2C8s ON PACLITAXEL, REPAGLINIDE AND IBUPROFEN ENANTIOMERS. Biopharm Drug Dispos 2013;34:278–87. https://doi.org/10.1002/bdd.1842.Search in Google Scholar PubMed
19. American Academy of Pediatric Dentistry. The reference manual of pediatric dentistry. Policy on pediatric dental pain management. Chicago, Ill: American Academy of Pediatric Dentistry; 2022.Search in Google Scholar
20. Lopezrodriguez, R, Novalbos, J, Gallegosandin, S, Romanmartinez, M, Torrado, J, Gisbert, J, 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;58:77–84. https://doi.org/10.1016/j.phrs.2008.07.004.Search in Google Scholar PubMed
21. Ochoa, D, Prieto-Pérez, R, Román, M, Talegón, M, Rivas, A, Galicia, I, et al.. Effect of gender and CYP2C9 and CYP2C8 polymorphisms on the pharmacokinetics of ibuprofen enantiomers. Pharmacogenomics 2015;16:939–48. https://doi.org/10.2217/pgs.15.40.Search in Google Scholar PubMed
22. Bagher, AM. Association of CYP2C9*3 and CYP2C8*3 non-functional alleles with ibuprofen-induced upper gastrointestinal toxicity in a Saudi patient. Case Rep Med 2023;2023:1–6. https://doi.org/10.1155/2023/6623269.Search in Google Scholar PubMed PubMed Central
23. Zobdeh, F, Eremenko, II, Akan, MA, Tarasov, VV, Chubarev, VN, Schiöth, HB, et al.. Pharmacogenetics and pain treatment with a focus on non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants: a systematic review. Pharmaceutics 2022;14:1190. https://doi.org/10.3390/pharmaceutics14061190.Search in Google Scholar PubMed PubMed Central
24. Bagher, AM, Alharbi, WS, Gadi, LS, Binmahfouz, LS, Hareeri, RH. Allelic variants in the Warfarin-related genes VKORC1 and CYP2C9 in a Western Saudi population. J Pharmacol Pharmacother 2023;14:125–32. https://doi.org/10.1177/0976500x231189351.Search in Google Scholar
25. Hong, EP, Park, JW. Sample size and statistical power calculation in genetic association studies. Genom Inf 2012;10:117. https://doi.org/10.5808/gi.2012.10.2.117.Search in Google Scholar PubMed PubMed Central
26. Cheng, X-R, Xia, P-G, Shi, Z-Y, Xu, Q-Y, Luo, C-H, Lei, M-Y, et al.. Increased risk of intracranial hemorrhage in preterm infants with OPRM1 gene A118G polymorphism. Ann Transl Med 2019;7:478. https://doi.org/10.21037/atm.2019.08.53.Search in Google Scholar PubMed PubMed Central
27. Minhas, S, Setia, N, Pandita, S, Saxena, R, Verma, IC, Aggarwal, S. Prevalence of CYP2C8 polymorphisms in a North Indian population. Genet Mol Res 2013;12:2260–6. https://doi.org/10.4238/2013.july.8.7.Search in Google Scholar
28. Camara, MD, Zhou, Y, De Sousa, TN, Gil, JP, Djimde, AA, Lauschke, VM. Meta-analysis of the global distribution of clinically relevant CYP2C8 alleles and their inferred functional consequences. Hum Genom 2024;18:40. https://doi.org/10.1186/s40246-024-00610-y.Search in Google Scholar PubMed PubMed Central
29. The 1000 Genomes Project Consortium, Auton, A, Brooks, LD, Durbin, RM, Garrison, EP, Kang, HM, et al.. A global reference for human genetic variation. Nature 2015;526:68–74. https://doi.org/10.1038/nature15393.Search in Google Scholar PubMed PubMed Central
30. General Authority for Statistics. Demography survey in Saudi Arabis; 2016. Available from: https://www.stats.gov.sa/sites/default/files/en-demographic-research-2016_2.pdf.Search in Google Scholar
31. Parikh, S, Ouedraogo, J-B, Goldstein, JA, Rosenthal, PJ, Kroetz, DL. Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa. Clin Pharmacol Ther 2007;82:197–203. https://doi.org/10.1038/sj.clpt.6100122.Search in Google Scholar PubMed
32. Bergmann, TK, Brasch-Andersen, C, Gréen, H, Mirza, M, Pedersen, RS, Nielsen, F, et al.. Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer. Pharmacogenomics J 2011;11:113–20. https://doi.org/10.1038/tpj.2010.19.Search in Google Scholar PubMed
33. Leskelä, S, Jara, C, Leandro-García, LJ, Martínez, A, García-Donas, J, Hernando, S, et al.. Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity. Pharmacogenomics J 2011;11:121–9. https://doi.org/10.1038/tpj.2010.13.Search in Google Scholar PubMed
34. Lazarska, KE, Dekker, SJ, Vermeulen, NPE, Commandeur, JNM. Effect of UGT2B7*2 and CYP2C8*4 polymorphisms on diclofenac metabolism. Toxicol Lett 2018;284:70–8. https://doi.org/10.1016/j.toxlet.2017.11.038.Search in Google Scholar PubMed
35. 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 Therapeut 2020;108:191–200. https://doi.org/10.1002/cpt.1830.Search in Google Scholar PubMed PubMed Central
© 2024 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- ‘Pharmacogenetics, health and ethnicity in Latin American populations’ call for the “Dr José María Cantú Award 2024”
- Reviews
- Current developments and advancements of 3-dimensional printing in personalized medication and drug screening
- Status of the implementation of pharmacogenetics in clinical practice in Spain: from regional to national initiatives
- Minireview
- CYP2C19 genotype-phenotype correlation: current insights and unanswered questions
- Original Articles
- Pediatric pharmacogenetics: profiling CYP2C8 polymorphisms at King Abdulaziz University Dental Clinic
- Optimizing tacrolimus therapeutic drug monitoring in Tunisian kidney transplant recipients: exploring the variability in bioavailability and the correlation between pharmacokinetic parameters
- Efficacy and safety of a polyherbal formulation in the management of Escherichia coli urinary tract infection
- UHPLC-MS/MS standardized extract of Vernonia amygdalina leaf inhibits CYP2C9 and CYP3A4 activities in hepatic cells of control and streptozotocin-induced diabetic rats
Articles in the same Issue
- Frontmatter
- Editorial
- ‘Pharmacogenetics, health and ethnicity in Latin American populations’ call for the “Dr José María Cantú Award 2024”
- Reviews
- Current developments and advancements of 3-dimensional printing in personalized medication and drug screening
- Status of the implementation of pharmacogenetics in clinical practice in Spain: from regional to national initiatives
- Minireview
- CYP2C19 genotype-phenotype correlation: current insights and unanswered questions
- Original Articles
- Pediatric pharmacogenetics: profiling CYP2C8 polymorphisms at King Abdulaziz University Dental Clinic
- Optimizing tacrolimus therapeutic drug monitoring in Tunisian kidney transplant recipients: exploring the variability in bioavailability and the correlation between pharmacokinetic parameters
- Efficacy and safety of a polyherbal formulation in the management of Escherichia coli urinary tract infection
- UHPLC-MS/MS standardized extract of Vernonia amygdalina leaf inhibits CYP2C9 and CYP3A4 activities in hepatic cells of control and streptozotocin-induced diabetic rats
