CYP2C19 GENOTYPES IN A POPULATION OF HEALTHY VOLUNTEERS AND IN CHILDREN WITH HEMATOLOGICAL MALIGNANCIES IN GAZA STRIP
Main Article Content
Keywords
CYP2C19, polymorphism, hematological malignancy, PCR-RFLP, Gaza Strip
Abstract
Background
Cytochrome P450 2C19 (CYP2C19) participates in the metabolism of many clinically important drugs and xenobiotic compounds. Genetic polymorphisms of the CYP2C19 gene are described to have possible effect on drug treatment and increasing susceptibility to carcinogenic substances. The aim of this study was to determine the frequencies of the common polymorphic CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) in Gaza Strip population and to investigate their association with occurrence of childhood hematological malignancies as compared to healthy subjects.
Methods
The polymorphism of CYP2C19 was analyzed by PCR-RFLP. DNA was extracted from blood samples obtained from 52 previously diagnosed hematological malignancy children and 200 normal subjects.
Results
In the patient group the frequencies of CYP2C19*2 and CYP2C19*3 were 9.62% and 0.96%, respectively; while in the control group the respective frequencies were 5.75% and 3%. There is no significant difference between the healthy and the patient groups in terms of the frequencies of CYP2C19*2 and CYP2C19*3. The genotyping analysis showed the following results: 15.39% (1*/2*), 1.92% (1*/3*), 1.92% (2*/2*) and 80.77% (1*/1*) in the patients, while in the normal subjects the distribution of CYP2C19*1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 genotypes were 86.5, 6.5, 3, 1.5, 2, and 0.5 %, respectively.
Conclusion
There is no significant association between the CYP2C19 polymorphism and the occurrence of the childhood hematological malignancies. The distribution of CYP2C19*2 in the Gaza Strip population is lower than that in Caucasians, Africans and the Asian populations. The CYP2C19*3 allele, which was not reported in the Caucasian populations, is present in 3% of the Gaza Strip population. Further studies are needed to investigate the role of other CYPs’ polymorphisms in our patient group.
References
2. Hukkanen J. Xenobiotic-metabolizing cytochrome p450 enzymes in human lung. e161 [dissertation]. University of Oulu publications. Oulu University, Finland;2000.
3. Guengerich FP. Cytochrome P450s and other enzymes in drug metabolism and toxicity. AAPS Journal 2006;8(1):E101-E111.
4. Mcginnity DF, Parker AJ, Soars M, Riley RJ. Automated definition of the enzymology of drug oxidation by the major human drug metabolizing cytochrome P450s. Drug Metab Dispos 2000;28(11):1327-1334.
5. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 1997;32:210-258.
6. Cribb AE, Spielberg SP, Griffin GP. N4Hydroxylation of sulfamethoxazole by cytochrome P450 of the cytochrome P4502C subfamily and reduction of sulfamethoxazole hydroxylamine in human and rat hepatic microsomes. Drug Metab Dispos 1995;23:406414.
7. Meehan RR, Gosden JR, Rout D, et al. Human cytochrome P-450 PB-I: a multigene family involved in mephenytoin and steroid oxidations that maps to chromosome
10. Am J Hum Genet 1988;42:26-37.
8. Ibeanu GC, Blaisdell J, Ferguson RJ, et al. A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin. J Pharmacol Exp Ther 1999;290(2):635-640.
9. Walker R. Clinical Pharmacy and Therapeutics. 3 rd ed. Churchill Livingstone;2002.
10. Pirmohamed M, Park BK. Genetic susceptibility to adverse drug reactions. Trends Pharmacol Sci 2001;22:298-305.
11. Human Cytochrome P450 (CYP) Allele Nomenclature Committee. Accessed June 2007. http://www.cypalleles.ki.se/cyp2c19. htm
12. Online Mendelian Inheritance in Man (OMIM). CYTOCHROME P450, SUBFAMILY IIC, POLYPEPTIDE 19; CYP2C19. Accessed August 2007. http://www.ncbi.nlm.nih.gov/entrez/dispomim.c gi?id=124020
13. Rodrigues AD, Rushmore TH. Cytochrome P450 pharmacogenetics in drug development: In Vitro studies and clinical consequences. Curr Drug Metab 2002;3(3):289-309.
14. He N, Yan FX, Huang SL, et al. CYP2C19 genotype and s-mephenytoin 4'-hydroxylation phenotype in a Chinese Dai population. Eur J Pharmacol 2002;58:15-18.
15. Shi WX, Chen SQ. Frequencies of poor metabolizers of cytochrome P450 2C19 in esophagus cancer, stomach cancer, lung cancer and bladder cancer in Chinese population. World J Gastroenterol 2004;10(13):1961-1963.
16. Haematological Malignancy Diagnostic Service (HMDS). Accessed August 2007. http://www.hmds.org.uk/
17. Bowen DT, Frew ME, Rollinson S, et al. CYP1A1*2B (Val) allele is overrepresented in a subgroup of acute myeloid leukemia patients with poor -risk karyotype associated with NRAS mutation, but not associated with FLT3 internal tandem duplication. Blood 2003;101(7):27702774.
18. Tamminga WJ, Wemer J, Oosterhuis B, de Zeeuw RA, de Leij LFMH, Jonkman JHG. The prevalence of CYP2D6 and CYP2C19 genotypes in a population of healthy Dutch volunteers and psychiatric patients. Eur J Clin Pharmacol 2001;57:712–722.
19. Wadelius M, Autrup JL, Stubbins MJ, et al. Polymorphisms in NAT2, CYP2D6, CYP2C19, and GSTP1 and their association with prostate cancer. Pharmocogenetics 1999;9(3):333-340.
20. Bartsch H, Nair U, Risch A, Rojas M, Wi kman H, Alexandrov K. Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers. Cancer Epidemiol Biomarkers Prev 2000;9(1):3-28.
21. Hamdy SI, Hiratsuka M, Narahara K, et al. Allele and genotype frequencies of polymorphic cytochromes P450 (CYP2C9, CYP2C19, CYP2E1) and dihydropyrimidine dehydrogenase (DPYD) in the Egyptian population. Br J Clin Pharmacol 2002;53(6):596-580.
22. Sviri S, Shpizen S, Leitersdorf E, Levy M, Caraco Y. Phenotypic genotypic analysis of CYP2C19 in the Jewish Israeli population. Clin Pharmacol Ther. 1999; 65(3):275-282.
23. Zand N, Tajik N, Hoormand M, Iraj MI. Allele frequency of CYP2C19 gene polymorphisms in a healthy Iranian population. Iranian Journal of Pharmacology & Therapeutics. 2006;4:124-128.
24. Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM, et al. Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics. 1997;7(1):59-64.
25. Lamba JK, Dhiman RK, Kohli KK. CYP2C19 genetic mutations in North Indians. Clin Pharmacol Ther. 2000;68:328–335.
26. Jurima RM, Goldstein JA, LeBelle M. CYP2C19 genotyping and associated mephenytoin hydroxylation polymorphism in a Canadian Inuit population. Pharmacogenetics. 1996; 6:329–339.
27. Yamada H, Dahl ML, Lannfelt L, Vitainen M, Winblad B. CYP2D6 and CYP2C19 genotypes in an elderly Swedish population. Eur J Clin Pharmacol. 1999;54:479–481.
28. Bathum L, Andersen RK, Boldsen J, Brosen K, Jeune B. Genotypes for the cytochrome P450 enzymes CYP2D6 and CYP2C19 in human longevity: role of CYP2D6 and CYP2C19 in longevity. Eur J Clin Pharmacol. 1998;54:427– 430.
29. Ozawa S, Soyama A, Saeki M, Fukushima- Uesaka H, Itoda M, Koyano S. Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1. Drug Metab Pharmacokinet. 2004;19:83-95.
30. Persson I, Aklillu E, Rodrigues F, Bertilsson L, Ingelman SM. S-mephenytoin hydroxylation phenotype and CYP2C19 genotype among Ethiopians. Pharmacogenetics. 1996;6:521–526.
31. Herrlin K, Massele AY, Jande M. Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype. Clin Pharmacol Ther. 1999;64:391–401.
32. Dandara C, Masimirembwa CM, Magimba A. Genetic polymorphism of CYP2D6, CYP2C19 in East, Southern African populations including psychiatric patients. Eur J Clin Pharmacol. 2001;75:11–17.
33. Chang M, Dahl ML, Tybring G, Gotharson E, Bertilsson L. Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics. 1995;5:358–363.
Article Sidebar
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.