Genetic polymorphisms of CYP2B6*6, CYP2C8*3 and CYP2D6*4 in vivax malaria patients from Brazilian Amazon

Authors

  • José Pereira de Moura Neto Faculdade de Ciências Farmacêuticas, Universidade Federal do Amazonas, Manaus, Amazonas, Brazil https://orcid.org/0000-0003-2177-7292
  • Jaquelane Silva de Jesus Faculdade de Ciências Farmacêuticas, Universidade Federal do Amazonas, Manaus, Amazonas, Brazil
  • Marcus Vinícius Guimarães de Lacerda Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brasil
  • Thiago de Jesus Bacha Faculdade de Ciências Farmacêuticas, Universidade Federal do Amazonas, Manaus, Amazonas, Brazil https://orcid.org/0000-0003-1314-5172
  • Igor Rafael dos Santos Magalhães Faculdade de Ciências Farmacêuticas, Universidade Federal do Amazonas, Manaus, Amazonas, Brazil https://orcid.org/0000-0002-0651-696X

DOI:

https://doi.org/10.1590/

Keywords:

Malaria;, Metabolism;, CYP;, Pharmacogenetics.

Abstract

Genetic variability in the host metabolism of antimalarial drugs influenced by the polymorphisms of cytochrome P450 (CYP) could lead to significant changes in antimalarial treatment response. However, little is known about the frequency of alleles CYP2B6, CYP2C8, and CYP2D6 in an Amazonian population, especially with vivax malaria. Therefore, this study aimed to determine the frequency of CYP alleles CYP2B6*6, CYP2C8*3, and CYP2D6*4 in patients with vivax malaria. The study included 231 patients with vivax malaria treated at a health care reference in Manaus, northern Brazil. A sample of peripheral blood from each subject was collected to perform DNA extraction and genotypic analysis. Genotyping of polymorphisms was performed by allelic discrimination using Real-time polymerase chain reaction. The CYP2D6*4 allele was the most prevalent among patients who developed severe malaria. The frequencies of the CYP2B6*6 and CYP2D6*4 were not different between the severe and uncomplicated malaria. There was a significant association between heterozygous CYP2D6*4 and severe cases of malaria. The results are in agreement with other reports described in the literature for different populations. Future studies are needed to understand the clinical implications of the polymorphisms in patients with vivax malaria.

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References

Alexandre MA, Ferreira CO, Siqueira AM, Magalhães BL, Mourão MP, Lacerda MV, et al. Severe Plasmodium vivax malaria, Brazilian Amazon. Emerg Infect Dis. 2010;16(10):1611-4.

Alves FP, Durlacher RR, Menezes MJ, Krieger H, Silva LH, Camargo EP. High prevalence of asymptomatic Plasmodium vivax and Plasmodium falciparum infections in native Amazonian populations. Am J Trop Med Hyg. 2002;66(6):641-8.

Bahadur N, Leathart JB, 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(11):1579-89.

Cavaco I, Piedade R, Gil JP, Ribeiro V. CYP2C8 polymorphism among the Portuguese. Clin Chem Lab Med. 2006;44(2):168-70.

Costa FT, Lopes SC, Ferrer M, Leite JÁ, Martin-Jaular L, Bernabeu M, et al. On cytoadhesion of Plasmodium vivax: raison d’être? Mem Inst Oswaldo Cruz. 2011;106 Suppl 1:79-84.

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(7):597-607.

Ganesan S, Tekwani BL, Sahu R, Tripathi LM, Walker LA. Cytochrome P(450)-dependent toxic effects of primaquine on human erythrocytes. Toxicol Appl Pharmacol. 2009;241(1):14-22.

Gounden V, van Niekerk C, Snyman T, George JA. Presence of the CYP2B6 516G> T polymorphism, increased plasma Efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients. AIDS Res Ther. 2010;7:32.

Guzmán V, Carmona-Fonseca J. El citocromo P-450 y la respuesta terapéutica a los antimaláricos [Cytochrome P-450 and the response to antimalarial drugs]. Rev Panam Salud Publica. 2006;19(1):9-22.

Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS. 2004;18(18):2391-400.

Hodel EMS, Csajka C, Ariey F, Guidi M, Kabanywanyi AM, Duong S, et al. Effect of single nucleotide polymorphisms in cytochrome P450 isoenzyme and n-acetyltransferase 2 genes on the metabolism of artemisinin-based combination therapies in malaria patients from Cambodia and Tanzania. Antimicrob Agents Chemother. 2013;57(2):950-8.

Honda M, Muroi Y, Tamaki Y, Saigusa D, Suzuki N, Tomioka Y, et al. Functional characterization of CYP2B6 allelic variants in demethylation of antimalarial artemether. Drug Metab Dispos. 2011;39(10):1860-5.

Ingelman-SundbergM,Rodriguez-AntonaC.Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy. Philos Trans R Soc Lond B Biol Sci. 2005;360(1460):1563-70.

Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007;116(3):496-526. doi: 10.1016/j.pharmthera.2007.09.004. Epub 2007 Oct 9.

» https://doi.org/10.1016/j.pharmthera.2007.09.004

Kerb R, Fux R, Mörike K, Kremsner PG, Gil JP, Gleiter CH, et al. Pharmacogenetics of antimalarial drugs: effect on metabolism and transport. Lancet Infect Dis. 2009;9(12):760-74.

Kim KA, Park JY, Lee JS, Lim S. Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes. Arch Pharm Res. 2003;26(8):631-7.

Kochar DK, Saxena V, Singh N, Kochar SK, Kumar SV, Das A. Plasmodium vivax malaria. Emerg Infect Dis. 2005;11(1):132-4. doi: 10.3201/eid1101.040519.

» https://doi.org/10.3201/eid1101.040519

Lang T, Klein K, Nüssler AK, Neuhaus P, Hofmann U, Eichelbaum M, et al. Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 2001;11(5):399-415.

Li XQ, Björkman A, Andersson TB, Gustafsson LL, Masimirembwa CM. Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol. 2003;59(5-6):429-42. doi: 10.1007/s00228-003-0636-9.

» https://doi.org/10.1007/s00228-003-0636-9

Maciel ME, Oliveira FK, Propst GB, Bicalho M da G, Cavalli IJ, Ribeiro EM de SF. Population analysis of xenobiotic metabolizing genes in South Brazilian Euro and Afro-descendants. Genet Mol Biol [Internet]. 2009;32(Genet. Mol. Biol., 2009 32(4)):723-8.

Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, et al, Hillman G, Fontecha MR, Lawrence HJ, Parker BA, Wu AH, Pierce JP. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin. 2011;89(5):718-25.

Mehlotra RK, Henry-Halldin CN, Zimmerman PA. Application of pharmacogenomics to malaria: a holistic approach for successful chemotherapy. Pharmacogenomics. 2009;10(3):435-49.

Muthiah YD, Lee WL, Teh LK, Ong CE, Ismail R. Genetic polymorphism of CYP2C8 in three Malaysian ethnics: CYP2C8*2 and CYP2C8*3 are found in Malaysian Indians. J Clin Pharm Ther. 2005;30(5):487-90.

Oliveira-Ferreira J, Lacerda MV, Brasil P, Ladislau JL, Tauil PL, Daniel-Ribeiro CT. Malaria in Brazil: an overview. Malar J. 2010;9:115.

Paganotti GM, Gallo BC, Verra F, Sirima BS, Nebié I, Diarra A, et al. Human genetic variation is associated with Plasmodium falciparum drug resistance. J Infect Dis. 2011;204(11):1772-8.

Parikh S, Ouedraogo JB, 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(2):197-203.

Projean D, Baune B, Farinotti R, Flinois JP, Beaune P, Taburet AM, et al. In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation. Drug Metab Dispos. 2003;31(6):748-54.

Pybus BS, Marcsisin SR, Jin X, Deye G, Sousa JC, Li Q, et al. The metabolism of primaquine to its active metabolite is dependent on CYP 2D6. Malar J. 2013;12:212.

Restrepo JG, Martínez C, García-Agúndez A, Gaviria E, Laguna JJ, García-Martín E, et al. Cytochrome P450 CYP2B6 genotypes and haplotypes in a Colombian population. Pharmacogenet Genomics. 2011;21(12):773-8.

Rodriguez-Antona C, Gomez A, Karlgren M, Sim SC, Ingelman-Sundberg M. Molecular genetics and epigenetics of the cytochrome P450 gene family and its relevance for cancer risk and treatment. Hum Genet. 2010;127(1):1-17.

Sachse C, Brockmöller J, Bauer S, Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet. 1997;60(2):284-95.

Stage TB, Christensen MMH, Feddersen S, Beck-Nielsen H, Brøsen K. The role of genetic variants in CYP2C8, LPIN1, PPARGC1A and PPARγ on the trough steady-state plasma concentrations of rosiglitazone and on glycosylated haemoglobin A1c in type 2 diabetes. Pharmacogenet Genomics 2013;23(4):219-27.

Suárez-Kurtz G, Pena SD, Struchner CJ, Hutz MH. Pharmacogenomic Diversity among Brazilians: Influence of Ancestry, Self-Reported Color, and Geographical Origin. Front Pharmacol. 2012;3:191.

Tomalik-Scharte D, Lazar A, Fuhr U, Kirchheiner J. The clinical role of genetic polymorphisms in drug-metabolizing enzymes. Pharmacogenomics J. 2008;8:4-15.

Tiong KH, Yiap BC, Tan EL, Ismail R, Ong CE. Functional characterization of cytochrome P450 2A6 allelic variants CYP2A6*15, CYP2A6*16, CYP2A6*21, and CYP2A6*22. Drug Metab Dispos. 2010;38(5):745-51.

Wang H, Tompkins LM. CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Curr Drug Metab. 2008;9(7):598-610.

Westenberger SJ, McClean CM, Chattopadhyay R, Dharia NV, Carlton JM, Barnwell JW, et al. A systems-based analysis of Plasmodium vivax lifecycle transcription from human to mosquito. PLoS Negl Trop Dis. 2010;4(4):e653.

World Health Organization. World Malaria Report. 2011.

WHO. Malaria - Drug Therapy. 2.Malaria - diagnosis. 3.Antimalarials - administration and dosage. 4. Drug Therapy, Combination. 5.Guideline. Third Edition: WHO, 2015.

Wu X, Zuo J, Guo T, Yuan L. CYP2C8 polymorphism frequencies among Han, Uighur, Hui, and Mongolian Chinese populations. Genet Test Mol Biomarkers. 2013;17(2):104-8.

Wyen C, Hendra H, Vogel M, Hoffmann C, Knechten H, Brockmeyer NH, et al. Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients. 2008;61(4):914-8.

Yusof W, Hua GS. Gene, ethnic and gender influences predisposition of adverse drug reactions to artesunate among Malaysians. Toxicol Mech Methods. 2012;22(3):184-92.

Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-41.

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Published

2023-11-17

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How to Cite

Genetic polymorphisms of CYP2B6*6, CYP2C8*3 and CYP2D6*4 in vivax malaria patients from Brazilian Amazon. (2023). Brazilian Journal of Pharmaceutical Sciences, 59, 8. https://doi.org/10.1590/