Expression and polymorphism (rs4880) of mitochondrial superoxide dismutase (SOD2) and asparaginase induced hepatotoxicity in adult patients with acute lymphoblastic leukemia

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Abstract

Asparaginase, which depletes asparagine and glutamine, activates amino-acid stress response. Oxidative stress mediated by excessive reactive oxygen species (ROS) causes enhanced mitochondrial permeabilization and subsequent cell apoptosis and is considered as a plausible mechanism for drug-induced hepatotoxicity, a common toxicity of asparaginase in adults with acute lymphoblastic leukemia (ALL). Studies investigating the pharmacogenetics of asparaginase in ALL are limited and focused on asparaginase-induced allergic reaction common in pediatric patients. Here, we sought to determine a potential association between the variant rs4880 in SOD2 gene, a key mitochondrial enzyme that protects cells against ROS, and hepatotoxicity during asparaginase-based therapy in 224 patients enrolled on CALGB-10102, a treatment trial for adults with ALL. We report that the CC genotype of rs4880 is associated with increased hepatotoxicity following asparaginase-based treatment. Thus, rs4880 likely contributes to asparaginase-induced hepatotoxicity, and functional studies investigating this single-nucleotide polymorphism (SNP) are needed to develop therapeutic approaches that mitigate this toxicity.

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References

  1. 1

    Stock W, Douer D, DeAngelo DJ, Arellano M, Advani A, Damon L et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma 2011; 52: 2237–2253.

  2. 2

    Chen SH, Pei D, Yang W, Cheng C, Jeha S, Cox NJ et al. Genetic variations in GRIA1 on chromosome 5q33 related to asparaginase hypersensitivity. Clin Pharmacol Ther 2010; 88: 191–196.

  3. 3

    Chen SH, Yang W, Fan Y, Stocco G, Crews KR, Yang JJ et al. A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity. Leukemia 2011; 25: 66–74.

  4. 4

    Rousseau J, Gagne V, Labuda M, Beaubois C, Sinnett D, Laverdiere C et al. ATF5 polymorphisms influence ATF function and response to treatment in children with childhood acute lymphoblastic leukemia. Blood 2011; 118: 5883–5890.

  5. 5

    Kearney SL, Dahlberg SE, Levy DE, Voss SD, Sallan SE, Silverman LB . Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis. Pediatr Blood Cancer 2009; 53: 162–167.

  6. 6

    Miao L St, Clair DK . Regulation of superoxide dismutase genes: implications in disease. Free Radic Biol Med 2009; 47: 344–356.

  7. 7

    Huang YS, Su WJ, Huang YH, Chen CY, Chang FY, Lin HC et al. Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury. J Hepatol 2007; 47: 128–134.

  8. 8

    Lucena MI, Garcia-Martin E, Andrade RJ, Martinez C, Stephens C, Ruiz JD et al. Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury. Hepatology 2010; 52: 303–312.

  9. 9

    Glynn SA, Boersma BJ, Howe TM, Edvardsen H, Geisler SB, Goodman JE et al. A mitochondrial target sequence polymorphism in manganese superoxide dismutase predicts inferior survival in breast cancer patients treated with cyclophosphamide. Clin Cancer Res 2009; 15: 4165–4173.

  10. 10

    Lee WM . Drug-induced hepatotoxicity. N Engl J Med 2003; 349: 474–485.

  11. 11

    Wilson GJ, Bunpo P, Cundiff JK, Wek RC, Anthony TG . The eukaryotic initiation factor 2 kinase GCN2 protects against hepatotoxicity during asparaginase treatment. Am J Physiol Endocrinol Metab 2013; 305: E1124–E1133.

  12. 12

    Costantini P, Jacotot E, Decaudin D, Kroemer G . Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst 2000; 92: 1042–1053.

  13. 13

    Choi JY, Nowell SA, Blanco JG, Ambrosone CB . The role of genetic variability in drug metabolism pathways in breast cancer prognosis. Pharmacogenomics 2006; 7: 613–624.

  14. 14

    Macmillan-Crow LA, Cruthirds DL . Invited review: manganese superoxide dismutase in disease. Free Radic Res 2001; 34: 325–336.

  15. 15

    Zelko IN, Mariani TJ, Folz RJ . Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med 2002; 33: 337–349.

  16. 16

    Fridovich I . Superoxide radical and superoxide dismutases. Annu Rev Biochem 1995; 64: 97–112.

  17. 17

    Lebovitz RM, Zhang H, Vogel H, Cartwright J Jr., Dionne L, Lu N et al. Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci USA 1996; 93: 9782–9787.

  18. 18

    Williams MD, Van Remmen H, Conrad CC, Huang TT, Epstein CJ, Richardson A . Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem 1998; 273: 28510–28515.

  19. 19

    Ong MM, Wang AS, Leow KY, Khoo YM, Boelsterli UA . Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2(+/-) mice. Free Radic Biol Med 2006; 40: 420–429.

  20. 20

    Larosche I, Letteron P, Berson A, Fromenty B, Huang TT, Moreau R et al. Hepatic mitochondrial DNA depletion after an alcohol binge in mice: probable role of peroxynitrite and modulation by manganese superoxide dismutase. J Pharmacol Exp Ther 2010; 332: 886–897.

  21. 21

    Sutton A, Khoury H, Prip-Buus C, Cepanec C, Pessayre D, Degoul F . The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics 2003; 13: 145–157.

  22. 22

    Ambrosone CB, Freudenheim JL, Thompson PA, Bowman E, Vena JE, Marshall JR et al. Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer. Cancer Res 1999; 59: 602–606.

  23. 23

    Woodson K, Tangrea JA, Lehman TA, Modali R, Taylor KM, Snyder K et al. Manganese superoxide dismutase (MnSOD) polymorphism, alpha-tocopherol supplementation and prostate cancer risk in the alpha-tocopherol, beta-carotene cancer prevention study (Finland). Cancer Causes Control 2003; 14: 513–518.

  24. 24

    Hung RJ, Boffetta P, Brennan P, Malaveille C, Gelatti U, Placidi D et al. Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis 2004; 25: 973–978.

  25. 25

    Pullarkat ST, Danley K, Bernstein L, Brynes RK, Cozen W . High lifetime incidence of adult acute lymphoblastic leukemia among Hispanics in California. Cancer Epidemiol Biomarkers Prev 2009; 18: 611–615.

  26. 26

    Bastaki M, Huen K, Manzanillo P, Chande N, Chen C, Balmes JR et al. Genotype-activity relationship for Mn-superoxide dismutase, glutathione peroxidase 1 and catalase in humans. Pharmacogenet Genomics 2006; 16: 279–286.

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Acknowledgements

We would like to thank the University of Chicago Cancer Research Foundation Women’s Board and Division of Biological Sciences. This work was also supported by the following grants: NIH grants: T32GM007019, UM1 CA186705 and P30 CA14599-36.

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Correspondence to W Stock.

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The authors declare no conflict of interest.

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Alachkar, H., Fulton, N., Sanford, B. et al. Expression and polymorphism (rs4880) of mitochondrial superoxide dismutase (SOD2) and asparaginase induced hepatotoxicity in adult patients with acute lymphoblastic leukemia. Pharmacogenomics J 17, 274–279 (2017) doi:10.1038/tpj.2016.7

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