Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter August 13, 2015

Association of ABCB1, ABCC5 and xanthine oxidase genetic polymorphisms with methotrexate adverse reactions in Mexican pediatric patients with ALL

  • Fausto Zaruma-Torres ORCID logo EMAIL logo , Ismael Lares-Asseff EMAIL logo , Aarón Reyes-Espinoza , Verónica Loera-Castañeda , Isaías Chairez-Hernández , Martha Sosa-Macías , Carlos Galaviz-Hernández and Horacio Almanza-Reyes


Background: Acute lymphoblastic leukemia (ALL) is one of the most frequent oncological disorders in pediatric populations. To date, the drug of choice for the treatment of ALL is methotrexate, a drug associated with a high risk of adverse reactions (ADRs). The xanthine oxidase (XO) polymorphisms, 1936A>G and 2107A>G, as well as the polymorphic variants derived from ATP-binding cassette transporter gene subfamilies, ABCB1 and ABCC5, of drug resistant codifying genes, are implicated as precursors of drug-related neurologic, hepatic, and renal toxicities. Our aim was to determine whether the mentioned polymorphisms are risk or protective factors for the development of adverse reactions by methotrexate in our pediatric population with ALL.

Methods: A total of 35 Mexican children from Centro Estatal de Cancerología-Durango, Mexico, with ALL and the previously noted polymorphisms as determined qPCR were studied. At the same time, a 12-month drug monitoring program was conducted in accordance with WHO-PAHO guidelines for pharmacovigilance.

Results: The ABCB11936A>G and 2107A>G and ABCC5 3414+434A>C polymorphisms were not associated with methotrexate ADRs. Single nucleotide polymorphisms (SNPs) of ABCB1 1236C>T (OR 0.19, 95% CI: 0.03–0.9, p<0.05) and ABCC5 3933+313T>C (OR 0.12, 95% CI: 0.027–0.58, p<0.05) were associated with methotrexate ADRs.

Conclusions: SNPs 1236C>T of ABCB1 and ABCC5 3933+313T>C are not associated with the development of typical ADRs by methotrexate, rather, they showed a protective factor for myelosuppression in the studied sick population.

Corresponding authors: Fausto Zaruma-Torres, Applied Genomic Academy of National Politechnic Institute, CIIDIR, Durango, Mexico, Phone: +52(618)8142091, Fax: +52(618)8144540, E-mail: .; School of Biochemistry and Pharmacy of University of Cuenca, Ecuador; and Ismael Lares-Asseff, Applied Genomic Academy of National Politechnic Institute, CIIDIR, Durango, Mexico, Phone: +52(618)8142091, Fax: +52(618)8144540, E-mail:


The authors acknowledge the following for their assistance with this research: Lic Pedro Cruz, Director General de Centro Oncológico Pediátrico de Baja California and Dr. Jesús Manuel Lozano García, Director Médico de Centro Oncológico Pediátrico of Baja California; Dr. Miguel Reyes-López of Centro de Biotecnología Genómica del IPN- Reynosa Tamaulipas, México; Anne Nafziger MD, PhD of Albany Medical Center, St Peter´s Hospital, NY, USA for review of manuscript and Dra. María Cristina Arias-Peláez of Departamento Fisiología-Universidad Juárez Estado Durango, México.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


1. Rodríguez L, González-Llano O, Mancias C, Pompa T, González G, Sandoval A, et al Observaciones sobre la incidencia de leucemias agudas en el Noreste de México. Rev Hematol Mex 2010;11:78–81.Search in Google Scholar

2. Website: Dirección General de Información en Salud(DGIS). Base de datos de egresos hospitalarios por mortalidad en instituciones públicas;Available at: Accessed 15 Oct 2014.Search in Google Scholar

3. Website: King MW. Introducción a las Membranas Biológicas; Available at: Accessed 14 Nov 2013.Search in Google Scholar

4. Higgins CF. ABC transporters: physiology, structure andmechanism – an overview. Res Microbiol 2011;152:205–210.10.1016/S0923-2508(01)01193-7Search in Google Scholar

5. Holland KA, Holland IB. Adventures with ABC-proteins: highly conserved ATP-dependent transporters. Acta Microbiol Inmunol Hung 2005;52:309–22.10.1556/AMicr.52.2005.3-4.4Search in Google Scholar

6. Gottesman M, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP–dependent transporters. Nat. Rev. Cancer 2005;2:48–58.Search in Google Scholar

7. Wielinga P, Hooijberg JH, Gunnarsdottir S, Kathmann l, Reid G, Zelcer N, et al.The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolates. Cancer Res 2005;65:4425–30.10.1158/0008-5472.CAN-04-2810Search in Google Scholar

8. Sanz-Sabrafen J, Besses- Raebel C, Vives-Corrons J, editors. Hematología Clínica, 5th ed. Madrid: Elsevier, 2006:889.Search in Google Scholar

9. Kremer J. Methotrexate pharmacogenomics. Ann Rheum Dis 2006;65:1121–3.10.1136/ard.2006.051789Search in Google Scholar

10. Liu Y, Yin Y, Sheng Q, Lu X, Wang F, Lin Z, et al. Association of ABCC2 224C.T Polymorphism with High-Dose Methotrexate Plasma Concentrations and Toxicities in Childhood Acute Lymphoblastic Leukemia. PloSone 2014:9:1–7.10.1371/journal.pone.0082681Search in Google Scholar

11. Kudo M, Sasaki T, Ishikawa M, Hirasawa N, Hiratsuka M. Kinetics of 6-Thioxanthine Metabolism by Allelic Variants of Xanthine Oxidase. Drug Metab Pharmacokinet 2010;25: 361–6.10.2133/dmpk.DMPK-10-RG-029Search in Google Scholar

12. Massey V, Komai H, Palmer G, Elion G. On the Mechanism of inactivation of Xanthine oxidase by allopurinol and other pyrazol[3,4-d]pyrimidines. J Biol Chem 1970;245:2837–44.10.1016/S0021-9258(18)63065-0Search in Google Scholar

13. Gregers J, Gréen H, Christensen IJ, Dalhoff K, Schroeder H, Carlsen N, et al. Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia. Pharmacogenomics J 2015;1–8.10.1038/tpj.2014.81Search in Google Scholar PubMed PubMed Central

14. Zgheib NK, Akra-Ismail M, Aridi C, Mahfouz R, Abboud MR, Solh H, et al. Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia. Pharmacogenet Genomics 2014;24:387–96.10.1097/FPC.0000000000000069Search in Google Scholar PubMed

15. Website: Haematology BSo. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia hme page. Available at: http// Accessed 01 Sep 2013.Search in Google Scholar

16. Pui C, Relling M, Sandlund J, Downing JR, Campana D, Evans WE, et al. Rationale and design of Total Therapy Study XV for newly diagnosed childhood acute lymphoblastic leukemia. Ann Hematol 2004;83:S124–6.Search in Google Scholar

17. Naranjo C, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–46.10.1038/clpt.1981.154Search in Google Scholar PubMed

18. Organización Panamericana de la Salud. Buenas Prácticas de Farmacovigilancia para las Américas. Vol Red PARF Documento Técnico No. 5. Washington D.C: 2010;OPS:78.Search in Google Scholar

19. SSA-COFEPRIS Guía de farmacovigilancia para la notificacion de sospecha de reacciones adversas/ Reacciones adversas. In: COFEPRIS, ed. MEXICO DF: 2012:21.Search in Google Scholar

20. World Health Organization.Safety of Medicines: a guide to detecting and reporting adverse drug reactions. Geneva: World Health Organization, 2002:20.Search in Google Scholar

21. National Cancer Institute-NCI. NCI Guidelines for investigators: Adverse event reporting requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs. NCI;2013: 34.Search in Google Scholar

22. Website: Institut Catalá d´Oncologia-ICO. SNPStats-Your web for SNP analysis. Available at:ña: Accessed: 04 Mar 2014.Search in Google Scholar

23. Levran O, O’Hara E, Peles K, Li D, Barral S, Ray B, et al. ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence. Hum Mol Genet 2008;17:2219–27.10.1093/hmg/ddn122Search in Google Scholar PubMed PubMed Central

24. Colom H, Farré R, Soy D, Peraire C, Cendros J, Pardo N, et al. Population pharmacokinetics of high-dose methotrexate after intravenous administration in pediatric patients with osteosarcoma. Ther Drug Monit 2009;31:76–85.10.1097/FTD.0b013e3181945624Search in Google Scholar PubMed

25. Tsuchiya N, Satoh S, Tada H, Li Z, Ohyama C, Sato K, et al . Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation. 2004;78:1182–7.10.1097/01.TP.0000137789.58694.B4Search in Google Scholar PubMed

26. Yates CR, Zhang W, Song P, Li S, Gaber A, Kotb M, et al. The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. J Clin Pharmacol 2003;43:555–64.10.1177/0091270003253617Search in Google Scholar

27. Kotnik, B, Grabnar I, Bohanec P, Dolzan V, Jazbec J. Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma. Eur J Clin Pharmacol 2011;67:993–1006.10.1007/s00228-011-1046-zSearch in Google Scholar PubMed

28. Erdιlyi D, Kamory E, Csokay B, Andrikovics H,Tordai A, Kiss C, et al. Synergistic interaction of ABCB1 and ABCG2 polymorphisms predicts the prevalence of toxic encephalopathy during anticancer chemotherapy. Pharmacogenomics J 2008;8:321–7.10.1038/sj.tpj.6500480Search in Google Scholar PubMed

29. Website:Biosystems LT-A. Real-Time PCR Assays. Available at: Accessed 2 Jan 2014.Search in Google Scholar

30. McAleer MA, Breen MA, White NL and Mathews N. pABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells. J Bio Chem 2009;274:23541–8.10.1074/jbc.274.33.23541Search in Google Scholar PubMed

31. Mor-Cohen R, Zivelin A, Rosenberg N, Shani M, Muallem S, Seligsohn U. Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. J Biol Chem 2001;276:36923–30.10.1074/jbc.M105047200Search in Google Scholar PubMed

32. Hawwa AF, Millership JS, Collier PS, Vandenbroeck K, McCarthy A, Dempsey S, et al. Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine. Br J Clin Pharmacol 2008;66:517–8.10.1111/j.1365-2125.2008.03248.xSearch in Google Scholar PubMed PubMed Central

33. Bowman W, Shuster J, Cook B, Griffin T. Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma. J Clin Oncol 1996;14:1252–62.10.1200/JCO.1996.14.4.1252Search in Google Scholar PubMed

Received: 2015-3-2
Accepted: 2015-7-14
Published Online: 2015-8-13
Published in Print: 2015-9-1

©2015 by De Gruyter

Downloaded on 25.9.2023 from
Scroll to top button