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Association between polymorphisms of EPHX1 and XRCC1 genes and the risk of childhood acute lymphoblastic leukemia

  • Toxicogenomics
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Abstract

Microsomal epoxide hydrolase, EPHX1, plays a central role in the detoxification of potentially genotoxic epoxide intermediates. In this study, we firstly aimed to investigate the relationship between EPHX1 Tyr113His and His139Arg variants, and the risk of incidence of childhood acute lymphoblastic leukemia (ALL) in Turkish population, comprised of 190 healthy controls and 167 ALL patients. In exon 3 Tyr113His polymorphism, 113His/His homozygous mutant genotype with slow activity was 18.6% in ALL patients and 9% in controls, indicating 113His/His slow activity genotype was significantly associated with an increased risk of childhood ALL (OR: 2.3, 95% CI, 1.2–4.4, P = 0.01). No significant association was found between exon 4 His139Arg variant and the risk of ALL. When both exon 3 Tyr113His and exon 4 His139Arg polymorphisms were considered together, only the exon 3 113His/His, homozygous mutant, slow activity genotype with exon 4 wild-type genotype 139His/His was significantly increased the risk of ALL 2.4-fold (OR: 2.4, P = 0.02). We also evaluated whether haplotype analysis for EPHX1 Tyr113His polymorphism together with DNA protein XRCC1 Arg399Gln variant known for its deficient DNA repair capacity would represent more prominent risk factors for the development of childhood ALL. Accordingly, the co-presence of Tyr113His variant of EPHX1 and Arg399Gln variant of XRCC1 in the same individuals significantly increased the risk of childhood ALL up to 2.1-fold (OR = 2.1, P = 0.03). Moreover, homozygous mutant genotype for both genes significantly and considerably increased the risk of childhood ALL 8.5-fold (OR: 8.5, P = 0.03). In conclusion, individuals with EPHX1 113His/His slow activity genotype may not detoxify reactive carcinogenic epoxides efficiently, binding of reactive epoxides to DNA cause DNA damage. With the inadequate polymorphic DNA repair protein, XRCC1, this situation ultimately leads to significantly increased susceptibility for childhood ALL.

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References

  • Alves S, Amorim A, Ferreira F, Norton L, Prata MJ (2002) The GSTM1 and GSTT1 genetic polymorphisms and susceptibility to acute lymphoblastic leukemia in children from north Portugal. Leukemia 16(8):1565–1567

    Article  PubMed  CAS  Google Scholar 

  • Arand M, Herrero Plana ME, Hengstler JG, Lohmann M, Cronin A, Oesch F (2003) Detoxification strategy of epoxide hydrolase-the basis for a threshold in chemical carcinogenesis. EXCLI J 2:22–30

    Google Scholar 

  • Arinç E (2010) The role of polymorphic cytochrome P450 enzymes in drug design, development and drug interactions with a special emphasis on phenotyping. J Mol Catal B Enzyme 64:120–122

    Article  Google Scholar 

  • Arinç E, Philpot RM (1976) Preparation and properties of partially purified pulmonary cytochrome P-450 from rabbits. J Biol Chem 251:3213–3220

    PubMed  Google Scholar 

  • Arinç E, Sen A (1994) Effects of in vivo benzo(a)pyrene treatment on liver microsomal mixed-function oxidase activities of gilthead seabream (Sparus aurata). Comp Biochem Physiol Pharmacol Toxicol Endocrinol 107(3):405–414

    Article  PubMed  Google Scholar 

  • Arinç E, Adalı O, İşcan M, Güray T (1991) Stimulatory effects of benzene on rabbit liver and kidney microsomal cytochrome P-450 drug metabolizing enzymes. Arch Toxicol 65:186–190

    Article  PubMed  Google Scholar 

  • Arinç E, Adalı O, Gencler-Ozkan AM (2000a) Induction of N-nitrosodimethylamine metabolism in liver and lung by in vivo pyridine treatments of rabbits. Arch Toxicol 74:329–334

    Article  PubMed  Google Scholar 

  • Arinç E, Adalı O, Gençler-Özkan AM (2000b) Stimulation of aniline, p-nitrophenol and N-nitrosodimethylamine metabolism in kidney by pyridine treatments of rabbits. Arch Toxicol 74:527–532

    Article  PubMed  Google Scholar 

  • Arinç E, Arslan S, Adali O (2005) Differential effects of diabetes on CYP2E1 and CYP2B4 proteins and associated drug metabolizing enzyme activities in rabbit liver. Arch Toxicol 79:427–433

    Article  PubMed  Google Scholar 

  • Arinç E, Arslan S, Bozcaarmutlu A, Adali O (2007) Effects of diabetes on rabbit kidney and lung CYP2E1 and CYP2B4 expression and drug metabolism and potentiation of carcinogenic activity of N-nitrosodimethylamine in kidney and lung. Food Chem Toxicol 45:107–118

    Article  PubMed  Google Scholar 

  • Bellucci G, Berti G, Chiappe C, Lippi A, Marioni F (1987) The metabolism of carbamazepine in humans: steric course of the enzymatic hydrolysis of the 10, 11-epoxide. J Med Chem 30:768–773

    Article  PubMed  CAS  Google Scholar 

  • Boccia S, Sayed-Tabatabaei FA, Persiani R, Gianfagna F, Rausei S, Arzani D, La Greca A, D’Ugo D, La Torre G, van Duijn CM, Ricciardi G (2007) Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population. BMC Cancer 7:206

    Article  PubMed  Google Scholar 

  • Bolufer P, Collado M, Barragán E, Cervera J, Calasanz MJ, Colomer D, Roman-Gómez J, Sanz MA (2007) The potential effect of gender in combination with common genetic polymorphisms of drug-metabolizing enzymes on the risk of developing acute leukemia. Haematologica 92(3):308–314

    Article  PubMed  CAS  Google Scholar 

  • Celkan T (2007) Çocukluk Çağı Akut Lenfoblastik Lösemisi. Klinik Gelişim 20(2):14–26

    Google Scholar 

  • Clavel JS, Bellec S, Rebouissou F, Menegaux J, Feunteun C, Bonaiti-Pellie A, Baruchel K, Kebaili A, Lambilliotte G, Leverger D, Sommelet B, Lescoeur P (2005) Childhood leukemia, polymorphisms of metabolism enzyme genes, and interactions with maternal tobacco, coffee and alcohol consumption during pregnancy. Eur J Cancer Prev 14:531–540

    Article  PubMed  Google Scholar 

  • Decker M, Arand M, Cronin A (2009) Mammalian epoxide hydrolases in xenobiotic metabolism and signalling. Arch Toxicol 83(4):297–318

    Article  PubMed  CAS  Google Scholar 

  • Erkisi Z, Yaylim-Eraltan I, Turna A, Görmüs U, Camlica H, Isbir T (2010) Polymorphisms in the microsomal epoxide hydrolase gene: role in lung cancer susceptibility and prognosis. Tumori 96:756–763

    PubMed  CAS  Google Scholar 

  • Falany CN, McQuiddy P, Kasper CB (1987) Structure and organization of the microsomal xenobiotic epoxide hydrolase gene. J Biol Chem 262:5924–5930

    PubMed  CAS  Google Scholar 

  • Friedberg T, Lollmann B, Becker R, Holler R, Oesch F (1994) The microsomal epoxide hydrolase has a single membrane signal anchor sequence which is dispensable for the catalytic activity ofthis protein. Biochem J 303(Pt 3):967–972

    PubMed  CAS  Google Scholar 

  • Fritz P, Behrle E, Zanger UM, Mürdter T, Schwarzmann P, Kroemer HK (1996) Immunohistochemical assessment of human microsomal epoxide hydrolase in primary and secondary liver neoplasm: a quantitative approach. Xenobiotica 26(1):107–116

    Article  PubMed  CAS  Google Scholar 

  • Goode EL, White KL, Vierkant RA, Phelan CM, Cunningham JM, Schildkraut JM et al (2011) Xenobiotic-metabolizing gene polymorphisms and ovarian cancer risk. Mol Carcinog 50(5):397–402

    Article  PubMed  CAS  Google Scholar 

  • Hassett C, Aicher L, Sidhu JS, Omiecinski CJ (1994) Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants. Hum Mol Genet 3:421–428

    Article  PubMed  CAS  Google Scholar 

  • Hengstler JG, Arand M, Herrero ME, Oesch F (1998) Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility. Recent Results Cancer Res 154:47–85

    Google Scholar 

  • Hoeijmakers JHJ (2001) Genome maintenance mechanisms for preventing cancer. Nature 411:366–374

    Article  PubMed  CAS  Google Scholar 

  • Jackson MA, Stack HF, Rice JM, Waters MD (2000) A review of the genetic and related effects of 1,3-butadiene in rodents and humans. Mutat Res 463:123–181

    Google Scholar 

  • Jain M, Tilak AR, Upadhyay R, Kumar A, Mittal B (2008) Microsomal epoxide hydrolase (EPHX1), slow (exon 3, 113His) and fast (exon 4, 139Arg) alleles confer susceptibility to squamous cell esophageal cancer. Toxicol Appl Pharmacol 230(2):247–251

    Article  PubMed  CAS  Google Scholar 

  • Johansson I, Ingelman-Sundberg M (1988) Benzene metabolism by ethanol-, acetone-, and benzene-inducible cytochrome P-450 (IIE1) in rat and rabbit liver microsomes. Cancer Res 48:5387–5390

    PubMed  CAS  Google Scholar 

  • Johansson I, Ingelman-Sundberg M (2011) Genetic polymorphism and toxicology—with emphasis on cytochrome P450. Toxicol Sci 120(1):1–13

    Article  PubMed  CAS  Google Scholar 

  • Khedhaier A, Hassen E, Bouaouina N, Gabbouj S, Ahmed SB, Chouchane L (2008) Implication of xenobiotic metabolizing enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) polymorphisms in breast carcinoma. BMC Cancer 8:109

    Article  PubMed  Google Scholar 

  • Kiss I, Orsós Z, Gombos K, Bogner B, Csejtei A, Tibold A, Varga Z, Pázsit E, Magda I, Zölyomi A, Ember I (2007) Association between allelic polymorphisms of metabolizing enzymes (CYP 1A1, CYP 1A2, CYP 2E1, mEH) and occurrence of colorectal cancer in Hungary. Anticancer Res 27(4C):2931–2937

    PubMed  CAS  Google Scholar 

  • Korhonen S, Romppanen EL, Hiltunen M, Helisalmi M, Punnonen K, Hippela M, Heinonen S (2003) Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are associated with polycystic ovary syndrome. Fertil Steril 79:1353–1357

    Article  PubMed  Google Scholar 

  • Krajinovic M, Labuda D, Richer C, Karimi S, Sinnett D (1999) Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms. Blood 93(5):1496–1501

    PubMed  CAS  Google Scholar 

  • Lahiri DK, Schnabel B (1993) DNA Isolation by a rapid method from human blood samples: effects of MgCl2, EDTA, storage time and temperature on DNA yield and quality. Biochem Genet 31(7/9):321–328

    Article  PubMed  CAS  Google Scholar 

  • Lanzkowsky P (2000) Leukemias. In: Lanzkowsky P (ed) Manual of peadiatric hematology and oncology, 3rd edn. Academic Press, San Diego, pp 359–411

  • Lunn RM, Langlois RG, Hsieh LL, Thompson CL, Bell DA (1999) XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. Cancer Res 59(11):2557–2661

    PubMed  CAS  Google Scholar 

  • McKinney PA, Alexander FE, Cartwright RA, Parker L (1991) Parental occupations of children with leukemia in west Cumbria, north Humberside, and Gateshead. BMJ 302:681–687

    Article  PubMed  CAS  Google Scholar 

  • Mittal RD, Srivastava DL (2007) Cytochrome P4501A1 and microsomal epoxide hydrolase gene polymorphisms: gene-environment interaction and risk of prostate cancer. DNA Cell Biol 26(11):791–798

    Article  PubMed  CAS  Google Scholar 

  • Nebert DW, Ingelman-Sundberg M, Daly AK (1999) Genetic epidemiology of environmental toxicity and cancer susceptibility: human allelic polymorphisms in drug metabolizing enzyme genes, their functional importance, and nomenclature issues. Drug Metab Rev 31(2):467–487

    Article  PubMed  CAS  Google Scholar 

  • Oesch F (1973) Mammalian epoxide hydrases: inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds. Xenobiotica 5:305–340

    Article  Google Scholar 

  • Recio L, Bauer A, Faiola B (2005) Use of genetically modified mouse models to assess pathways of benzene-induced bone marrow cytotoxicity and genotoxicity. Chem Biol Interact 153–154:159–164

    Article  PubMed  Google Scholar 

  • Ribera JM, Oriol A (2009) Acute lymphoblastic leukemia in adolescents and young adults. Hematol Oncol Clin North Am 23(5):1033–1042

    Article  PubMed  Google Scholar 

  • Ross JA, Davies SM, Potter JD, Robison LL (1994) Epidemiology of childhood leukemia with a focus on infants. Epidemiol Rev 16:243–272

    PubMed  CAS  Google Scholar 

  • Silveira Vda S, Canalle R, Scrideli CA, Queiroz RG, Tone LG (2009) Role of the CYP2D6, EPHX1, MPO, and NQO1 genes in the susceptibility to acute lymphoblastic leukemia in Brazilian children. Environ Mol Mutagen 51(1):48–56

    Google Scholar 

  • Sirma S, Agaoglu L, Yildiz I, Cayli D, Horgusluoglu E, Anak S, Yuksel L, Unuvar A, Celkan T, Apak H, Karakas Z, Devecioglu O, Ozbek U (2004) NAD(P)H: quinone oxidoreductase 1 null genotype is not associated with pediatric de novo acute leukemia. Pediatr Blood Cancer 43(5):568–570

    Article  PubMed  Google Scholar 

  • Smith CAD, Harrison DJ (1997) Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema. Lancet 350:630–633

    Article  PubMed  CAS  Google Scholar 

  • Srivastava DS, Mandhani A, Mittal RD (2008) Genetic polymorphisms of cytochrome P450 CYP1A1 (*2A) and microsomal epoxide hydrolase gene, interactions with tobacco-users, and susceptibility to bladder cancer: a study from North India. Arch Toxicol 82(9):633–639

    Article  PubMed  CAS  Google Scholar 

  • Tilak AR, Kumar S, Jain M, Pant MC, Das BC, Guleria R et al (2011) Association of functionally important polymorphism of microsomal epoxide hydrolase gene (EPHX1) with lung cancer susceptibility. Cancer Invest 29(6):411–418

    Article  PubMed  CAS  Google Scholar 

  • Tumer TB, Ulusoy G, Adali O, Sahin G, Gozdasoglu S, Arinç E (2007) The low frequency of defective TPMT alleles in Turkish population: a study on pediatric patients with acute lymphoblastic leukemia. Am J Hematol 82(10):906–910

    Article  PubMed  CAS  Google Scholar 

  • Tumer TB, Yilmaz D, Tanrikut C, Sahin G, Ulusoy G, Arinç E (2010) DNA repair XRCC1 Arg399Gln polymorphism alone, and in combination with CYP2E1 polymorphisms significantly contribute to the risk of development of childhood acute lymphoblastic leukemia. Leuk Res 34(10):1275–1281

    Article  PubMed  CAS  Google Scholar 

  • Ulusoy G, Adali O, Tumer TB, Sahin G, Gozdasoglu S, Arinç E (2007a) Significance of genetic polymorphisms at multiple loci of CYP2E1 in the risk of development of childhood acute lymphoblastic leukemia. Oncology 72(1–2):125–131

    Article  PubMed  CAS  Google Scholar 

  • Ulusoy G, Arinç E, Adali O (2007b) Genotype and allele frequencies of polymorphic CYP2E1in the Turkish population. Arch Toxicol 10:711–718

    Article  Google Scholar 

  • Vidal AE, Boiteux S, Hickson ID, Radicella JP (2001) XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein–protein interactions. EMBO J 20:6530–6539

    Article  PubMed  CAS  Google Scholar 

  • Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW (2001) XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell 104:107–117

    Article  PubMed  CAS  Google Scholar 

  • Wickliffe JK, Ammenheuser MM, Salazar JJ, Abdel-Rahman SZ, Hastings-Smit DA, Postlethwait EM, Lloyd RS, Ward JB (2003) A model of sensitivity: 1,3-butadiene increases mutant frequencies and genomic damage in mice lacking a functional microsomal epoxide hydrolase gene. Environ Mol Mutagen 2:106–110

    Article  Google Scholar 

  • Wickliffe JF, Herring SM, Hallberg LM, Galbert LA, Masters OE, Ammenheuser MM, Xie J, Friedberg EC, Lloyd RS, Abdel Rahman SZ, Ward JB (2007) Detoxification of olefinic epoxides and nucleotide excision repair of epoxide-mediated DNA damage: insights from animal models examining human sensitivity to 1,3-butadiene. Chem Biol Interact 20:226–231

    Article  Google Scholar 

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Acknowledgments

The authors thank to the healthy volunteers and patients for participating to the study. This study was partially supported by Turkish Academy of Sciences.

Conflict of interest

We have no conflict of interest whether of a financial or other nature.

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Authors and Affiliations

  1. Biochemistry Graduate Programme and Department of Biological Sciences, Middle East Technical University, Ankara, 06531, Turkey

    Tugba Boyunegmez Tumer & Emel Arinç

  2. Vocational College of Health Services, Canakkale Onsekiz Mart University, Canakkale, Turkey

    Tugba Boyunegmez Tumer

  3. Department of Oncology, Dr. Sami Ulus Children’s Hospital, Ankara, Turkey

    Gurses Sahin

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  1. Tugba Boyunegmez Tumer
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  2. Gurses Sahin
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Correspondence to Emel Arinç.

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Tumer, T.B., Sahin, G. & Arinç, E. Association between polymorphisms of EPHX1 and XRCC1 genes and the risk of childhood acute lymphoblastic leukemia. Arch Toxicol 86, 431–439 (2012). https://doi.org/10.1007/s00204-011-0760-8

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