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The influence of polymorphisms in the drug transporter, ABCB1 on the toxicity of glucocorticoids in Saudi children with acute lymphoblastic leukaemia

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Abstract

Background

Glucocorticoids play essential roles in the treatment of childhood acute lymphoblastic leukaemia (ALL); however, treatment with these agents can result in severe side-effects. This study, the first of its kind in a Saudi population, investigates associations of ABCB1 gene polymorphisms (pharmacodynamics and pharmacokinetic) with the development of toxicity and side effects (glucose abnormality, liver toxicity and infection) in a small population of Saudi children with ALL.

Methods

Three single nucleotide polymorphisms (SNPs) of the ABCB1 gene (rs 3213619 T129C, rs 2032582 G2677T and rs1045642 C3435T) were analysed in 70 Saudi children with ALL and 60 control subjects. Participants were treated according to the ALL 2000 study protocol. Toxicities were assessed and associations with genotypes were evaluated according to Common Toxicity Criteria (NCI-CTC).

Results

Significant associations were observed among carriers and the mutated genotype C3435T (ABCB1), which had an incidence of infection (p  = 0.05). Although no correlations were found between liver toxicity and glucose abnormalities for patients carrying ABCB1 SNPs, risk factors for liver toxicity were elevated by a factor of three for patients carrying the SNP G2677T, OR 3.00 (1.034–8.702). The risk factor of glucose abnormality toxicity for the patients carring T129C were increased three times OR 3.06 (0.486–19.198).

Conclusions

In terms of infection incidence, polymorphism C3435T may contribute to potential life-threatening infections during paediatric ALL therapy, through glucocorticoid usage.

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References

  1. Marino S, Verzegnassi F, Tamaro P, Stocco G, Bartoli F, Decorti G, et al. Response to glucocorticoids and toxicity in childhood acute lymphoblastic leukemia: role of polymorphisms of genes involved in glucocorticoid response. Pediatr Blood Cancer 2009;53:984–91, doi: https://doi.org/10.1002/pbc.22163.

    Article  PubMed  Google Scholar 

  2. Cheok MH, Pottier N, Kager L, Evans WE. Pharmacogenetics in acute lymphoblastic leukemia. Semin Hematol 2009;46:39–51, doi: https://doi.org/10.1053/j.seminhematol.2008.09.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Klein I, Sarkadi B, Váradi A. An inventory of the human ABC proteins. Biochim Biophys Acta 1999;1461:237–62.

    Article  CAS  PubMed  Google Scholar 

  4. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene 2003;22:7468–85, doi: https://doi.org/10.1038/sj.onc.1206948.

    Article  CAS  PubMed  Google Scholar 

  5. Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 2009;323:1718–22, doi: https://doi.org/10.1126/science.1168750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989;86:695–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Saito K, Miyake S, Moriya H, Yamazaki M, Itoh F, Imai K, et al. Detection of the four sequence variations of MDR1 gene using TaqMan MGB probe based realtime PCR and haplotype analysis in healthy Japanese subjects. Clin Biochem 2003;36:511–8.

    Article  CAS  PubMed  Google Scholar 

  8. van Helvoort A, Smith AJ, Sprong H, Fritzsche I, Schinkel AH, Borst P, et al. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 1996;87:507–17.

    Article  PubMed  Google Scholar 

  9. Leschziner GD, Andrew T, Pirmohamed M, Johnson MR. ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenomics J 2007;7:154–79, doi: https://doi.org/10.1038/sj.tpj.6500413.

    Article  CAS  PubMed  Google Scholar 

  10. Siegsmund M, Brinkmann U, Scháffeler E, Weirich G, Schwab M, Eichelbaum M, et al. Association of the P-glycoprotein transporter MDR1(C3435T) polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol 2002;13:1847–54.

    Article  CAS  PubMed  Google Scholar 

  11. Roberts RL, Joyce PR, Mulder RT, Begg EJ, Kennedy MA. A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression. Pharmacogenomics J 2002;2:191–6, doi: https://doi.org/10.1038/sj.tpj.6500099.

    Article  CAS  PubMed  Google Scholar 

  12. Schwab M, Schaeffeler E, Marx C, Fromm MF, Kaskas B, Metzler J, et al. Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology 2003;124:26–33, doi: https://doi.org/10.1053/gast.2003.50010.

    Article  CAS  PubMed  Google Scholar 

  13. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 2001;70:189–99, doi: https://doi.org/10.1067/mcp.2001.117412.

    Article  CAS  PubMed  Google Scholar 

  14. Estrela R de C, Ribeiro FS, Barroso PF, Tuyama M, Gregório SP, Dias-Neto E, et al. ABCB1 polymorphisms and the concentrations of lopinavir and ritonavir in blood, semen and saliva of HIV-infected men under antiretroviral therapy. Pharmacogenomics 2009;10:311–8, doi: https://doi.org/10.2217/14622416.10.2.311.

    Article  Google Scholar 

  15. Oselin K, Gerloff T, Mrozikiewicz PM, Pähkla R, Roots I. MDR1 polymorphisms G2677T in exon 21 and C3435T in exon 26 fail to affect rhodamine 123 efflux in peripheral blood lymphocytes. Fundam Clin Pharmacol 2003;17:463–9.

    Article  CAS  PubMed  Google Scholar 

  16. Hemauer SJ, Nanovskaya TN, Abdel-Rahman SZ, Patrikeeva SL, Hankins GDV, Ahmed MS. Modulation of human placental P-glycoprotein expression and activity by MDR1 gene polymorphisms. Biochem Pharmacol 2010;79:921–5, doi: https://doi.org/10.1016/j.bcp.2009.10.026.

    Article  CAS  PubMed  Google Scholar 

  17. Gaffo A, Saag KG, Curtis JR. Treatment of rheumatoid arthritis. Am J Health Syst Pharm 2006;63:2451–65, doi: https://doi.org/10.2146/ajhp050514.

    Article  CAS  PubMed  Google Scholar 

  18. Inaba H, Pui C-H. Glucocorticoid use in acute lymphoblastic leukaemia. Lancet Oncol 2010;11:1096–106,doi: https://doi.org/10.1016/S1470-2045(10)70114–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Van Staa TP, Leufkens HGM, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. June, 2000. J Bone Miner Res 2005;20:1487–94, doi: https://doi.org/10.1359/jbmr.2005.20.8.1486 discussion 1486.

    PubMed  Google Scholar 

  20. Franklin J, Lunt M, Bunn D, Symmons D, Silman A. Risk and predictors of infection leading to hospitalisation in a large primary-care-derived cohort of patients with inflammatory polyarthritis. Ann Rheum Dis 2007;66:308–12, doi: https://doi.org/10.1136/ard.2006.057265.

    Article  PubMed  Google Scholar 

  21. Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 2006;54:628–34, doi: https://doi.org/10.1002/art.21568.

    Article  CAS  PubMed  Google Scholar 

  22. https://doi.org/ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcv2nom-4-30-99-final3.pdf. [Accessed 11 April 2018].

  23. Kawabata A, Momoi Y, Inoue-Murayama M, Iwasaki T. Canine mdr1 gene mutation in Japan. J Vet Med Sci 2005;67:1103–7.

    Article  CAS  PubMed  Google Scholar 

  24. Becker DE. Basic and clinical pharmacology of glucocorticosteroids. Anesth Prog 2013;60:25–31, doi: https://doi.org/10.2344/0003-3006-60.1.25.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Chang W-C. Pharmacogenomics in personalized medicine and drug metabolism. Biomed Res Int 2014;2014:897963, doi: https://doi.org/10.1155/2014/897963.

    PubMed  PubMed Central  Google Scholar 

  26. Kaya P, Gündüz U, Arpaci F, Ural AU, Guran S. Identification of polymorphisms on the MDR1 gene among Turkish population and their effects on multidrug resistance in acute leukemia patients. Am J Hematol 2005;80:26–34, doi: https://doi.org/10.1002/ajh.20427.

    Article  CAS  PubMed  Google Scholar 

  27. Fung KL, Gottesman MM. A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta 2009;1794:860–71, doi: https://doi.org/10.1016/j.bbapap.2009.02.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gümüş-Akay G, Rüstemoǧlu A, Karadag A, Sunguroǧlu A. Genotype and allele frequencies of MDR1 gene C1236T polymorphism in a Turkish population. Genet Mol Res 2008;7:1193–9.

    Article  PubMed  Google Scholar 

  29. Zhou S-F. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 2008;38:802–32, doi: https://doi.org/10.1080/00498250701867889.

    Article  CAS  PubMed  Google Scholar 

  30. Kimchi-Sarfaty C, Oh JM, Kim I-W, Sauna ZE, Calcagno AM, Ambudkar SV, et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 2007;315:525–8, doi: https://doi.org/10.1126/science.1135308.

    Article  CAS  PubMed  Google Scholar 

  31. Liu Y-Y, Li C, Cui Z, Fu X, Zhang S, Fan L-L, et al. The effect of ABCB1 C3435T polymorphism on pharmacokinetics of tacrolimus in liver transplantation: a meta-analysis. Gene 2013;531:476–88, doi: https://doi.org/10.1016/j.gene.2013.09.024.

    Article  CAS  PubMed  Google Scholar 

  32. Urayama KY, Ma X, Buffler PA. Exposure to infections through day-care attendance and risk of childhood leukaemia. Radiat Prot Dosimetry 2008;132:259–66, doi: https://doi.org/10.1093/rpd/ncn271.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Leal-Ugarte E, Gutiérrez-Angulo M, Macías-Gómez NM, Peralta-Leal V, Durán-González J, De La Luz Ayala-Madrigal M, et al. MDR1 C3435T polymorphism in Mexican children with acute lymphoblastic leukemia and in healthy individuals. Hum Biol 2008;80:449–55, doi: https://doi.org/10.3378/1534-6617-80.4.449.

    Article  PubMed  Google Scholar 

  34. Zhai X, Wang H, Zhu X, Miao H, Qian X, Li J, et al. Gene polymorphisms of ABC transporters are associated with clinical outcomes in children with acute lymphoblastic leukemia. Arch Med Sci 2012;8:659–71, doi: https://doi.org/10.5114/aoms.2012.30290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yue Q, Xiong B, Chen L, Chen Y, Bu F, Liu X, et al. MDR1 C3435T polymorphism and childhood acute lymphoblastic leukemia susceptibility: an updated meta-analysis. Biomed Pharmacother 2015;69:76–81, doi: https://doi.org/10.1016/j.biopha.2014.10.015.

    Article  CAS  PubMed  Google Scholar 

  36. Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S, et al. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res 2002;62:4955–62.

    CAS  PubMed  Google Scholar 

  37. Kurzawski M, Pawlik A, Górnik W, Drozdzik M. Frequency of common MDR1 gene variants in a Polish population. Pharmacol Rep 2006;58:35–40.

    CAS  PubMed  Google Scholar 

  38. Rao DN, Anuradha C, Vishnupriya S, Sailaja K, Surekha D, Raghunadharao D, et al. Association of an MDR1 gene (C3435T) polymorphism with acute leukemia in India. Asian Pac J Cancer Prev 2010;11:1063–6.

    PubMed  Google Scholar 

  39. Daniel JA, Yoo J, Bettinger BT, Amberg DC, Burke DJ. Eliminating gene conversion improves high-throughput genetics in Saccharomyces cerevisiae. Genetics 2006;172:709–11, doi: https://doi.org/10.1534/genetics.105.047662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, et al. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics 2011;21:152–61, doi: https://doi.org/10.1097/FPC.0b013e3283385a1c.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Enabah D, El Baz H, Moselhy H. Higher frequency of C.3435 of the ABCB1 gene in patients with tramadol dependence disorder. Am J Drug Alcohol Abuse 2014;40:317–20, doi: https://doi.org/10.3109/00952990.2014.925468.

    Article  PubMed  Google Scholar 

  42. Beaudet L, Gros P. Functional dissection of P-glycoprotein nucleotide-binding domains in chimeric and mutant proteins. Modulation of drug resistance profiles. J Biol Chem 1995;270:17159–70.

    Article  CAS  PubMed  Google Scholar 

  43. Kumar A, Angel JB, Aucoin S, Creery WD, Daftarian MP, Cameron DW, et al. Dysregulation of B7.2 (CD86) expression on monocytes of HIV-infected individuals is associated with altered production of IL-2. Clin Exp Immunol 1999;117:84–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jytothirmaye P, Lingumpelly R. Impact of genetic polymorphisms of MDR1 gene in the chemotherapeutic treatment of cervical cancer: a case control study. IJTPR 2015;7:85–91.

    Google Scholar 

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Authors and Affiliations

  1. Medical Laboratory Technology Department, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah, Saudi Arabia

    Refaat I. ElFayoumi, Adel Abozenadaha, Mamdouh Gari, Thoraia Shinawi, Talaat Mirza & Waleed Bawazir

  2. Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt

    Refaat I. ElFayoumi

  3. Clinical Pharmacology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

    Magda M. Hagras

  4. Pediatric Oncology Department, King Fisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia

    Ibrahim Abosoudah

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  1. Refaat I. ElFayoumi
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Correspondence to Refaat I. ElFayoumi or Magda M. Hagras.

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ElFayoumi, R.I., Hagras, M.M., Abozenadaha, A. et al. The influence of polymorphisms in the drug transporter, ABCB1 on the toxicity of glucocorticoids in Saudi children with acute lymphoblastic leukaemia. Pharmacol. Rep 71, 90–95 (2019). https://doi.org/10.1016/j.pharep.2018.09.010

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  • DOI: https://doi.org/10.1016/j.pharep.2018.09.010

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