Characterization and prevalence of polymorphisms of CYP2C8 and CYP2C9 pharmacognosy involved in the metabolism of non-steroidal anti-inflammatory drugs in a northern Mexican population
Keywords:
CYP2C8, CYP2C9, polymorphisms, NSAID, Mexican population.Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a group of drugs that differ in their therapeutic efficacy and toxicity. The P450 superfamily (CYP) enzyme system is the main system involved in the metabolism of these drugs. Different polymorphisms in the CYP2C8 and CYP2C9 genes code for this enzyme system, which is involved in the first metabolic steps of these drugs, which is reflected in the bioavailability, pharmacokinetics and risk of adverse events. There is a wide variation of frequencies in different ethnic groups for genetic variants in CYP2C8 and CYP2C9. For this reason, the objective of this research was to report the frequencies of the *1, *2 and *3 alleles of the CYP2C8 and CYP2C9 genes in a mestizo Mexican population residing in northern Mexico. Additionally, we compare these allelic frequencies with those reported in other regions
232 blood samples from mestizo Mexican individuals from northern Mexico, were analyzed and genotyped with the Affymetrix Axiom® Precision Medicine Research Array (PMRA) with approximately 900,000 SNPs. The frequency report was made by direct counting and compared with other Mexican and world populations. In this way, the polymorphisms of the CYP2C8 and CYP2C9 genes were characterized. The allele frequencies found were CYP2C9*1= 88.1% (normal), CYP2C9*2=8.0% (inactive), CYP2C9*3=3.9% (inactive), CYP2C8*1=88.8% (normal), CYP2C8*2=2.2% (inactive) and CYP2C8*3=5.2% (inactive). For CYP2C8, 18 genotypes (3.8%) generated could not be determined due to ambiguities at the time of identification.
In this study, it was possible to find genotypic and phenotypic frequencies similar to those reported in the Mexican population, but with a wide variability in the frequencies of the different alleles corresponding to the CYP2C8 and CYP2C9 genes for other ethnic groups; Given the wide variability of the drug efficacy and potential adverse events related to them, the foundation of this molecular information will allow us to use genomic data in the clinical processes of patients and the practice of precision medicine, and in this way be able to classify individuals according to their ability to metabolize NSAIDs, which will not only be reflected in expecting a better therapeutic response but also in estimating the probability of the risk of adverse events due to these drugs in each individual.
References
Adehin, A., Bolaji, O. O., & Kennedy, M. A. (2017). Polymorphisms in CYP2C8 and CYP3A5 genes in the Nigerian population. Drug metabolism and pharmacokinetics, 32(3), 189-191.
Aguilar, B., Rojas, J. C., & Collados, M. T. (2008). Prevalence of CYP2C9 variants in the Mexican population. Archives of medical research, 4(39), 463.
Agúndez, J. A., García-Martín, E., & Martínez, C. (2009). Genetically based impairment in CYP2C8-and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: is a combination of pharmacogenomics and metabolomics required to improve personalized medicine? Expert opinion on drug metabolism & toxicology, 5(6), 607-620.
Alcazar-González, G. A., Calderón-Garcidueñas, A. L., Garza-Rodríguez, M. L., Rubio-Hernández, G., Escorza-Treviño, S., Olano-Martin, E., . . . Le Brun, S. (2013). Comparative study of polymorphism frequencies of the CYP2D6, CYP3A5, CYP2C8 and IL-10 genes in Mexican and Spanish women with breast cancer. Pharmacogenomics, 14(13), 1583-1592.
Arnaldo, P., Thompson, R. E., Lopes, M. Q., Suffys, P. N., & Santos, A. R. (2013). Frequencies of cytochrome P450 2B6 and 2C8 allelic variants in the Mozambican population. The Malaysian Journal of Medical Sciences: MJMS, 20(4), 13.
Bae, J.-W., Kim, J.-H., Choi, C.-I., Kim, M.-J., Kim, H.-J., Byun, S., . . . Lee, S.-Y. (2009). Effect of CYP2C9* 3 allele on the pharmacokinetics of naproxen in Korean subjects. Archives of pharmacal research, 32(2), 269-273.
Bae, J. W., Choi, C. I., Jang, C. G., & Lee, S. Y. (2011). Effects of CYP2C9* 1/* 13 on the pharmacokinetics and pharmacodynamics of meloxicam. British journal of clinical pharmacology, 71(4), 550-555.
Cuautle‑Rodríguez, P., Rodríguez‑Rivera, N., De Andrés, F., Castillo‑Nájera, F., Llerena, A., & Molina‑Guarneros, J. A. (2019). Frequency of CYP2C9 (* 2,* 3 and IVS8‑109A> T) allelic variants, and their clinical implications, among Mexican patients with diabetes mellitus type 2 undergoing treatment with glibenclamide and metformin. Biomedical Reports, 10(5), 283-295.
Dorado, P., Sosa-Macias, M. G., Peñas-Lledó, E., Alanis-Bañuelos, R., Wong, M., Licinio, J., . . . Llerena, A. (2011). CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards. The pharmacogenomics journal, 11(2), 108-112.
Dorji, P. W., Wangchuk, S., Boonprasert, K., Tarasuk, M., & Na-Bangchang, K. (2019). Pharmacogenetic relevant polymorphisms of CYP2C9, CYP2C19, CYP2D6, and CYP3A5 in Bhutanese population. Drug Metabolism and Personalized Therapy, 34(4).
Ganoci, L., Božina, T., Skvrce, N. M., Lovrić, M., Mas, P., & Božina, N. (2017). Genetic polymorphisms of cytochrome P450 enzymes: CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in the Croatian population. Drug Metabolism and Personalized Therapy, 32(1), 11-21.
García-Martín, E., Martínez, C., Ladero, J. M., & Agúndez, J. A. (2006). Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals. Molecular diagnosis & therapy, 10(1), 29-40.
García‐Martín, E., Martínez, C., Tabarés, B., Frías, J., & Agúndez, J. A. (2004). Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clinical Pharmacology & Therapeutics, 76(2), 119-127.
Guardado-Estrada, M., Queipo, G., Meraz-Ríos, M., & Berumen-Campos, J. (2008). Diversidad genética en la población mexicana: Utilización de marcadores de ADN. Rev Med Hosp Gen Mex, 71(3), 162-174.
Gustincich, S., Manfioletti, G., Del Sal, G., Schneider, C., & Carninci, P. (1991). A fast method for high-quality genomic DNA extraction from whole human blood. Biotechniques, 11(3), 298-300, 302.
Kirchheiner, J., Störmer, E., Meisel, C., Steinbach, N., Roots, I., & Brockmöller, J. (2003). Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics and Genomics, 13(8), 473-480.
López-Rodríguez, R., Novalbos, J., Gallego-Sandín, S., Román-Martínez, M., Torrado, J., Gisbert, J. P., & Abad-Santos, F. (2008). Influence of CYP2C8 and CYP2C9 polymorphisms on pharmacokinetic and pharmacodynamic parameters of racemic and enantiomeric forms of ibuprofen in healthy volunteers. Pharmacological research, 58(1), 77-84.
Martínez, C., García‐Martín, E., Blanco, G., Gamito, F. J., Ladero, J. M., & Agúndez, J. A. (2005). The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)‐ibuprofen enantiomer in healthy subjects. British journal of clinical pharmacology, 59(1), 62-68.
Mescher, M., & Haarmann-Stemmann, T. (2018). Modulation of CYP1A1 metabolism: From adverse health effects to chemoprevention and therapeutic options. Pharmacology & Therapeutics, 187, 71-87.
Nebert, D. W., Wikvall, K., & Miller, W. L. (2013). Human cytochromes P450 in health and disease. Philosophical Transactions of the Royal Society B: Biological Sciences, 368(1612), 20120431.
Panchenko, E., Kropacheva, E., Dobrovolsky, A., Titaeva, E., Zemlyanskaya, O., Trofimov, D., . . . Sinitsin, S. (2020). CYP2C9 and VKORC1 genotyping for the quality of long-standing warfarin treatment in Russian patients. The pharmacogenomics journal, 20(5), 687-694.
Pedersen, R. S., Brasch-Andersen, C., Sim, S. C., Bergmann, T. K., Halling, J., Petersen, M. S., . . . Brøsen, K. (2010). Linkage disequilibrium between the CYP2C19* 17 allele and wildtype CYP2C8 and CYP2C9 alleles: identification of CYP2C haplotypes in healthy Nordic populations. European journal of clinical pharmacology, 66(12), 1199-1205.
Perini, J. A., Vianna‐Jorge, R., Brogliato, A. R., & Suarez‐Kurtz, G. (2005). Influence of CYP2C9 genotypes on the pharmacokinetics and pharmacodynamics of piroxicam. Clinical Pharmacology & Therapeutics, 78(4), 362-369.
Rollason, V., Flora Samer, C., Daali, Y., & Alexandre Desmeules, J. (2014). Prediction by pharmacogenetics of safety and efficacy of non-steroidal anti-inflammatory drugs: a review. Current drug metabolism, 15(3), 326-343.
Saldaña-Cruz, A. M., León-Moreno, L. C., Sánchez-Corona, J., Santiago, D. A. M.-d., Mendoza-Carrera, F., Castro-Martínez, X. H., . . . Flores-Martínez, S. E. (2016). CYP2C9 and CYP2C19 allele and haplotype distributions in four Mestizo populations from Western Mexico: an interethnic comparative Study. Genetic Testing and Molecular Biomarkers, 20(11), 702-709.
Sánchez-Pozos, K., Rivera-Santiago, C., García-Rodríguez, M. H., Ortiz-López, M. G., Peña-Espinoza, B. I., Granados-Silvestre, M. d. l. Á., . . . Menjívar, M. (2016). Genetic variability of CYP2C9* 2 and CYP2C9* 3 in seven indigenous groups from Mexico. Pharmacogenomics, 17(17), 1881-1889.
Santes-Palacios, R., Ornelas-Ayala, D., Cabañas, N., Marroquín-Pérez, A., Hernández-Magaña, A., del Rosario Olguín-Reyes, S., . . . Espinosa-Aguirre, J. J. (2016). Regulation of human cytochrome P4501A1 (hCYP1A1): a plausible target for chemoprevention? BioMed Research International, 2016.
Sim, S. C., & Ingelman-Sundberg, M. (2010). The Human Cytochrome P450 (CYP) Allele Nomenclature website: a peer-reviewed database of CYP variants and their associated effects. Human genomics, 4(4), 1-4.
Skadrić, I., & Stojković, O. (2020). Defining screening panel of functional variants of CYP1A1, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 genes in Serbian population. International Journal of Legal Medicine, 134(2), 433-439.
Sosa-Macías, M., & LLerena, A. (2013). Cytochrome P450 genetic polymorphisms of Mexican indigenous populations. Drug metabolism and drug interactions, 28(4), 193-208.
Sostres, C., Gargallo, C. J., & Lanas, A. (2013). Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis research & therapy, 15(3), 1-8.
Stamer, U. M., & StÜber, F. (2007). The pharmacogenetics of analgesia. Expert opinion on pharmacotherapy, 8(14), 2235-2245.
Urrutia, L. A. M., Laytén, G. S., & Velarde, O. F. (2008). Perfil del consumidor de antiinflamatorios no esteroideos en Chiclayo y Cajamarca, Perú. Acta médica peruana, 25(4), 216-219.
Vargens, D. D., Petzl‐Erler, M. L., & Suarez‐Kurtz, G. (2012). Distribution of CYP2C polymorphisms in an Amerindian population of Brazil. Basic and Clinical Pharmacology and Toxicology, 110(4), 396.
Vicente, J., González-Andrade, F., Soriano, A., Fanlo, A., Martínez-Jarreta, B., & Sinués, B. (2014). Genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 in Ecuadorian Mestizo and Spaniard populations: a comparative study. Molecular biology reports, 41(3), 1267-1272.
Wang, D., Dai, D.-P., Wu, H., Chong, J., Lü, Y., Yin, R., . . . Chen, H. (2020). Effects of rare CYP2C9 alleles on stable warfarin doses in Chinese Han patients with atrial fibrillation. Pharmacogenomics, 21(14), 1021-1031.
Wyatt, J., Pettit, W., & Harirforoosh, S. (2012). Pharmacogenetics of nonsteroidal anti-inflammatory drugs. The pharmacogenomics journal, 12(6), 462-467.
Xie, H.-G., Prasad, H. C., Kim, R. B., & Stein, C. M. (2002). CYP2C9 allelic variants: ethnic distribution and functional significance. Advanced drug delivery reviews, 54(10), 1257-1270.
Xing, S., Wang, Y., He, X., Yang, W., Hu, Q., He, Y., . . . Jin, T. (2021). CYP2C8 and CYP2E1 genetic variants increase risk of tuberculosis in northwest Chinese Han population. Infection, Genetics and Evolution, 95, 105022.
Yasar, Ü., Eliasson, E., Forslund-Bergengren, C., Tybring, G., Gadd, M., Sjöqvist, F., & Dahl, M.-L. (2001). The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro. European journal of clinical pharmacology, 57(10), 729-735.
Yin, S.-J., Qi, H.-M., Wang, X., Zhang, P., Lu, Y., Wei, M.-J., . . . Lu, C. (2017). Effects of functional CYP2C8, CYP2C9, CYP3A5, and ABCB1 genetic variants on the pharmacokinetics of insulin sensitizer pioglitazone in Chinese Han individuals. Pharmacogenetics and Genomics, 27(4), 125-134.
