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Hydroxyurea in the management of sickle cell disease: pharmacogenomics and enzymatic metabolism

The Pharmacogenomics Journal volume 18, pages 730–739 (2018)Cite this article

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Abstract

Hydroxyurea (HU) was approved to be used in the treatment of sickle cell disease (SCD) because of its anti-sickling potential. However, there is variability in HU response among SCD patients and this can be due to physiological, socioeconomic, environmental, metabolic and/or genetic factors. The present review focuses on the latter two. Three quantitative trait loci, HBG2, BCL11A and HMIP, have been suggested as important markers for HU response. Other genes (ASS1, KLF10, HAO2, MAP3K5, PDE7B, TOX, NOS1, NOS2A, FLT1, ARG1, ARG2, UGT1A1, OR51B5/6, SIN3A, SALL2, SAR1A, UTB, OCTN1, CYP2C9, AQP9, MPO, CYP2E1, and GSTT1) have also been considered. Studies implicate catalase, urease, horseradish peroxidase and enzymes of CYP450 family in HU metabolism. However, little is known about these enzymes. Therefore, further studies are needed to elucidate the metabolic pathway of HU, which will facilitate pharmacogenomic studies and help in identification of candidate genes for predicting HU response.

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References

  1. Villani P, Maserati R, Regazzi MB, Giacchino R, Lori F. Pharmacokinetics of hydroxyurea in patients infected with human immunodeficiency virus type I. J Clin Pharmacol. 1996;36:117–21.

    Article  CAS  Google Scholar 

  2. Opacic N, Zorc B, Cetina M, Mrvos-Sermek D, Raic-Malic S, Mintas M. Synthesis and X-ray crystal structure study of the hydroxyurea and hydantoin derivatives of l-valine. J Pept Res. 2005;66:85–93.

    Article  CAS  Google Scholar 

  3. Dalton RN, Turner C, Dick M, Height SE, Awogbade M, Inusa B, et al. The measurement of urinary hydroxyurea in sickle cell anaemia. Br J Haematol. 2005;130:138–44.

    Article  CAS  Google Scholar 

  4. Latagliata R, Spadea A, Cedrone M, Di Giandomenico J, De Muro M, Villivà N, et al. Gruppo Laziale SMPC Ph1 neg. Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome-negative myeloproliferative neoplasms: the Mister Hyde face of a safe drug. Cancer . 2012;118:404–9.

    Article  CAS  Google Scholar 

  5. Lori F, Lisziewicz J. Rationale for the use of hydroxyurea as an anti-human immunodeficiency virus drug. Clin Infect Dis. 2000;30:S193–7.

    Article  CAS  Google Scholar 

  6. Sassi H, Bachir D, Habibi A, Astier A, Galactéros F, Hulin A. No effect of CYP450 and P-glycoprotein on hydroxyurea in vitro metabolism. Fundam Clin Pharmacol. 2010;24:83–90.

    Article  CAS  Google Scholar 

  7. Lori F, Malykh A, Cara A, Sun D, Weinstein JN, Lisziewicz J, et al. Hydroxyurea as an inhibitor of human immuunodeficiency virus type 1 replication. Sci New Ser. 1994;266:801–5.

    CAS  Google Scholar 

  8. Restituto P, Mugueta C, Alegre E, Monreal JI, Varo N. Analytical interference of hydroxyurea in the determination of urea, uric acid, and lactic acid. Anal Biochem. 2006;357:147–9.

    Article  CAS  Google Scholar 

  9. King SB. The nitric oxide producing reactions of hydroxyurea. Curr Med Chem. 2003;10:437–52.

    Article  CAS  Google Scholar 

  10. Huang J, Yakubu M, Kim-Shapiro DB, King SB. Rat liver-mediated metabolism of hydroxyurea to nitric oxide. Free Radic Biol Med. 2006;40:1675–81.

    Article  CAS  Google Scholar 

  11. Kolliopoulou A, Stratopoulos A, Siamoglou S, Sgourou A, Ali BR, Papachatzopoulou A, et al. Key pharmacogenomic considerations for sickle cell disease patients. OMICS J Integr Biol. 2017;21:314–22.

    Article  CAS  Google Scholar 

  12. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376:2018–31.

    Article  CAS  Google Scholar 

  13. Silva-Pinto AC, Angulo IL, Brunetta DM, Neves FIR, Bassi SC, Santis GCD, et al. Clinical and hematological effects of hydroxyurea therapy in sickle cell patients: a single-center experience in Brazil. Sao Paulo Med J. 2013;131:238–43.

    Article  Google Scholar 

  14. Ma Q, Wyszynski DF, Farrell JJ, Kutlar A, Farrer LA, Baldwin CT, et al. Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea. Pharm J. 2007;7:386–94.

    CAS  Google Scholar 

  15. Gravia A, Chondrou V, Sgourou A, Papantoni I, Borg J, Katsila T, et al. Individualizing fetal hemoglobin augmenting therapy for β-type hemoglobinopathies patients. Pharmacogenomics. 2014;15:1355–64.

    Article  CAS  Google Scholar 

  16. Andrae U. Evidence for the involvment of cytochrome P-450-dependent monooxygenase(s) in the formation of genotoxic metabolites from N-hydroxyurea. Biochem Biophys Res Commun. 1984;118:409–15.

    Article  CAS  Google Scholar 

  17. Banan M. Hydroxyurea treatment in β-thalassemia patients: to respond or not to respond? Ann Hematol. 2013;92:289–99.

    Article  CAS  Google Scholar 

  18. Božina N, Bradamante V, Lovrić M. Genetic polymorphism of metabolic enzymes P450 (CYP) as a susceptibility factor for drug response, toxicity, and cancer risk. Arch Ind Hyg Toxicol. 2009;60:217–42.

    Google Scholar 

  19. Kumkhaek C, Taylor JG, Zhu J, Hoppe C, Kato GJ, Rodgers GP. Fetal haemoglobin response to hydroxycarbamide treatment and sar1a promoter polymorphisms in sickle cell anaemia. Br J Haematol. 2008;141:254–9.

    Article  CAS  Google Scholar 

  20. Friedrisch JR, Sheehan V, Flanagan JM, Baldan A, Summarell CCG, Bittar CM, et al. The role of BCL11A and HMIP-2 polymorphisms on endogenous and hydroxyurea induced levels of fetal hemoglobin in sickle cell anemia patients from southern Brazil. Blood Cells Mol Dis. 2016;62:32–7.

    Article  CAS  Google Scholar 

  21. Adekile A, Menzel S, Gupta R, Al-Sharida S, Farag A, Haider M, et al. Response to hydroxyurea among Kuwaiti patients with sickle cell disease and elevated baseline HbF levels: HU among Kuwaiti patients with SCD. Am J Hematol. 2015;90:E138–E139.

    Article  Google Scholar 

  22. Green NS, Ender KL, Pashankar F, Driscoll C, Giardina PJ, Mullen CA. et al. Candidate sequence variants and fetal hemoglobin in children with sickle cell disease treated with hydroxyurea. PLoS ONE. 2013;8:e55709.

    Article  CAS  Google Scholar 

  23. Aleluia MM, Santiago RP, da Guarda CC, Fonseca TCC, Neves FI, Quinto RS, et al. Genetic modulation of fetal hemoglobin in hydroxyurea-treated sickle cell anemia. Am J Hematol. 2017;92:E70–E72.

    Article  Google Scholar 

  24. Wonkam A, Ngo Bitoungui VJ, Vorster AA, Ramesar R, Cooper RS, Tayo B, et al. Association of variants at BCL11A and HBS1L-MYB with hemoglobin F and hospitalization rates among sickle cell patients in cameroon. PLoS One. 2014;9:e92506.

    Article  Google Scholar 

  25. Banan M, Bayat H, Azarkeivan A, Mohammadparast S, Kamali K, Farashi S, et al. The XmnI and BCL11A single nucleotide polymorphisms may help predict hydroxyurea response in Iranian β-thalassemia patients. Hemoglobin. 2012;36:371–80.

    Article  CAS  Google Scholar 

  26. Motovali-Bashi M, Ghasemi T. Role of XmnIgG polymorphism in hydroxyurea treatment and fetal hemoglobin level at Isfahanian intermediate β-thalassemia patients. Iran Biomed J. 2015;19:177–82.

    PubMed  PubMed Central  Google Scholar 

  27. Ali N, Ayyub M, Khan SA, Ahmed S, Abbas K, Malik HS, et al. Frequency of Gγ-globin promoter −158 (C > T) XmnI polymorphism in patients with homozygous/compound heterozygous beta thalassaemia. Hematol Oncol Stem Cell Ther. 2015;8:10–5.

    Article  CAS  Google Scholar 

  28. Karimi M, Haghpanah S, Farhadi A, Yavarian M. Genotype–phenotype relationship of patients with β-thalassemia taking hydroxyurea: a 13-year experience in Iran. Int J Hematol. 2012;95:51–6.

    Article  CAS  Google Scholar 

  29. Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, Smeltzer MP, et al. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood. 2011;118:4985–91.

    Article  CAS  Google Scholar 

  30. Solovieff N, Milton JN, Hartley SW, Sherva R, Sebastiani P, Dworkis DA, et al. Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5′ olfactory receptor gene cluster. Blood. 2010;115:1815–22.

    Article  CAS  Google Scholar 

  31. Akinsheye I, Solovieff N, Ngo D, Malek A, Sebastiani P, Steinberg MH, et al. Fetal hemoglobin in sickle cell anemia: molecular characterization of the unusually high fetal hemoglobin phenotype in African Americans. Am J Hematol. 2012;87:217–9.

    Article  CAS  Google Scholar 

  32. Cardoso GL, Diniz IG, Martins da Silva ANL, Cunha DA, da Silva Junior JS, Carvalho Uchôa CT, et al. DNA polymorphisms at BCL11A, HBS1L-MYB and Xmn1-HBG2 site loci associated with fetal hemoglobin levels in sickle cell anemia patients from Northern Brazil. Blood Cells Mol Dis. 2014;53:176–9.

    Article  CAS  Google Scholar 

  33. Tafrali C, Paizi A, Borg J, Radmilovic M, Bartsakoulia M, Giannopoulou E, et al. Genomic variation in the MAP3K5 gene is associated with β-thalassemia disease severity and hydroxyurea treatment efficacy. Pharmacogenomics. 2013;14:469–83.

    Article  CAS  Google Scholar 

  34. Atkins GB, Jain MK. Role of Kruppel-like transcription factors in endothelial biology. Circ Res. 2007;100:1686–95.

    Article  CAS  Google Scholar 

  35. Gravia A, Chondrou V, Kolliopoulou A, Kourakli A, John A, Symeonidis A, et al. Correlation of SIN3A genomic variants with β-hemoglobinopathies disease severity and hydroxyurea treatment efficacy. Pharmacogenomics. 2016;17:1785–93.

    Article  CAS  Google Scholar 

  36. Borg J, Phylactides M, Bartsakoulia M, Tafrali C, Lederer C, Felice AE, et al. KLF10 gene expression is associated with high fetal hemoglobin levels and with response to hydroxyurea treatment in β-hemoglobinopathy patients. Pharmacogenomics. 2012;13:1487–500.

    Article  CAS  Google Scholar 

  37. Kalra IS, Alam MM, Choudhary PK, Pace BS. Krüppel-like Factor 4 activates HBG gene expression in primary erythroid cells: KLF4 activates HBG gene transcription. Br J Haematol. 2011;154:248–59.

    Article  CAS  Google Scholar 

  38. Elalfy MS, El Sherif NHK, Kamal TM, Aly NH. Klf10 gene, a secondary modifier and a pharmacogenomic biomarker of hydroxyurea treatment among patients with hemoglobinopathies. J Pediatr Hematol Oncol. 2017;39:e155–e162.

    Article  CAS  Google Scholar 

  39. Sheehan VA, Crosby JR, Sabo A, Mortier NA, Howard TA, Muzny DM, et al. Whole exome sequencing identifies novel genes for fetal hemoglobin response to hydroxyurea in children with sickle cell anemia. PLoS One. 2014;9:e110740.

    Article  Google Scholar 

  40. Pule GD, Mowla S, Novitzky N, Wiysonge CS, Wonkam A. A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease. Expert Rev Hematol. 2015;8:669–79.

    Article  CAS  Google Scholar 

  41. Tang DC, Zhu J, Liu W, Chin K, Sun J, Chen L, et al. The hydroxyurea-induced small GTP-binding protein SAR modulates gamma-globin gene expression in human erythroid cells. Blood. 2005;106:3256–63.

    Article  CAS  Google Scholar 

  42. Karimi M, Zarei T, Haghpanah S, Moghadam M, Ebrahimi A, Rezaei N, et al. Relationship between some single-nucleotide polymorphism and response to hydroxyurea therapy in Iranian patients with β-thalassemia intermedia. J Pediatr Hematol Oncol. 2017;39:e171–e176.

    Article  CAS  Google Scholar 

  43. Chalikiopoulou C, Tavianatou A-G, Sgourou A, Kourakli A, Kelepouri D, Chrysanthakopoulou M, et al. Genomic variants in the ASS1 gene, involved in the nitric oxide biosynthesis and signaling pathway, predict hydroxyurea treatment efficacy in compound sickle cell disease/β-thalassemia patients. Pharmacogenomics. 2016;17:393–403.

    Article  CAS  Google Scholar 

  44. Olives B, Neau P, Bailly P, Hediger MA, Rousselet G, Cartron JP, et al. Cloning and functional expression of a urea transporter from human bone marrow cells. J Biol Chem. 1994;269:31649–52.

    CAS  PubMed  Google Scholar 

  45. Kobayashi D, Aizawa S, Maeda T, Tsuboi I, Yabuuchi H, Nezu J, et al. Expression of organic cation transporter OCTN1 in hematopoietic cells during erythroid differentiation. Exp Hematol. 2004;32:1156–62.

    Article  CAS  Google Scholar 

  46. Walker AL, Steward S, Howard TA, Mortier N, Smeltzer M, Wang Y-D, et al. Epigenetic and molecular profiles of erythroid cells after hydroxyurea treatment in sickle cell anemia. Blood. 2011;118:5664–70.

    Article  CAS  Google Scholar 

  47. Walker AL, Ofori-Acquah SF. Sustained enhancement of OCTN1 transporter expression in association with hydroxyurea induced γ-globin expression in erythroid progenitors. Exp Hematol. 2017;45:69–73.e2.

    Article  CAS  Google Scholar 

  48. Wyszynski DF, Baldwin CT, Cleves M, Farrell JJ, Bisbee A, Kutlar A, et al. Genetic polymorphisms associated with fetal hemoglobin response to hydroxyurea in patients with sickle cell anemia. Blood. 2004;104:108.

    Google Scholar 

  49. SCMA Yahouédéhou, MOS Carvalho, Oliveira RM, Santiago RP, da Guarda CC, Carvalho SP, et al. Sickle cell anemia patients in use of hydroxyurea: association between polymorphisms in genes encoding metabolizing drug enzymes and laboratory parameters. Dis Markers. 2018;2018:1–11.

    Google Scholar 

  50. Joly P, Renoux C, Lacan P, Bertrand Y, Cannas G, Garnier N, et al. UGT1A1 (TA)n genotype is not the major risk factor of cholelithiasis in sickle cell disease children. Eur J Haematol. 2017;98:296–301.

    Article  CAS  Google Scholar 

  51. Italia KY, Jijina FF, Jain D, Merchant R, Nadkarni AH, Mukherjee M, et al. The effect of UGT1A1 promoter polymorphism on bilirubin response to hydroxyurea therapy in hemoglobinopathies. Clin Biochem. 2010;43:1329–32.

    Article  CAS  Google Scholar 

  52. Heeney MM, Howard TA, Zimmerman SA, Ware RE. UGT1A promoter polymorphisms influence bilirubin response to hydroxyurea therapy in sickle cell anemia. J Lab Clin Med. 2003;141:279–82.

    Article  CAS  Google Scholar 

  53. Adekile A, Kutlar F, McKie K, Addington A, Elam D, Holley L, et al. The influence of uridine diphosphate glucuronosyl transferase 1A promoter polymorphisms, beta S-globin gene haplotype, co-inherited alpha-thalassemia trait and Hb F on steady-state serum bilirubin levels in sickle cell anemia. Eur J Haematol. 2005;75:150–5.

    Article  CAS  Google Scholar 

  54. Panigrahi I, Dixit A, Arora S, Kabra M, Mahapatra M, Choudhry VP, et al. Do alpha deletions influence hydroxyurea response in thalassemia intermedia? Hematology. 2005;10:61–3.

    Article  CAS  Google Scholar 

  55. Yavarian M, Karimi M, Bakker E, Harteveld CL, Giordano PC. Response to hydroxyurea treatment in Iranian transfusion-dependent beta-thalassemia patients. Haematologica. 2004;89:1172–8.

    CAS  PubMed  Google Scholar 

  56. Alebouyeh M, Moussavi F, Haddad-Deylami H, Vossough P. Hydroxyurea in the treatment of major beta-thalassemia and importance of genetic screening. Ann Hematol. 2004;83:430–3.

    Article  CAS  Google Scholar 

  57. Crittenden SC, Gilbert JE, Callen JP. Hydroxyurea-induced leg ulceration in a patient with a homozygous MTHFR polymorphism misdiagnosed as pyoderma gangrenosum. JAMA Dermatol. 2014;150:780.

    Article  Google Scholar 

  58. Adamson RH, Ague SL, Hess SM, Davidson JD. The distribution, excretion and metabolism of hydroxyurea-C14. J Pharmacol Exp Ther. 1965;150:322–7.

    CAS  PubMed  Google Scholar 

  59. Colvin M, Bono VH. The enzymatic reduction of hydroxyurea to urea by mouse liver. Cancer Res. 1970;30:1516–9.

    CAS  PubMed  Google Scholar 

  60. Fishbein WN, Winter TS, Davidson JD. Urease catalysis: I. Stoichiometry, specificity, and kinetics of a second substrate: hydroxyurea. J Biol Chem. 1965;240:2402–6.

    CAS  PubMed  Google Scholar 

  61. Jiang J, Jordan SJ, Barr DP, Gunther MR, Maeda H, Mason RP. In vivo production of nitric oxide in rats after administration of hydroxyurea. Mol Pharmacol. 1997;52:1081–6.

    Article  CAS  Google Scholar 

  62. Lockamy VL, Huang J, Shields H, Ballas SK, King SB, Kim-Shapiro DB. Urease enhances the formation of iron nitrosyl hemoglobin in the presence of hydroxyurea. Biochim Biophys Acta. 2003;1622:109–16.

    Article  CAS  Google Scholar 

  63. King SB. N-hydroxyurea and acyl nitroso compounds as nitroxyl (HNO) and nitric oxide (NO) donors. Curr Top Med Chem. 2005;5:665–73.

    Article  CAS  Google Scholar 

  64. Gladwin MT, Shelhamer JH, Ognibene FP, Pease-Fye ME, Nichols JS, Link B, et al. Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease. Br J Haematol. 2002;116:436–44.

    Article  CAS  Google Scholar 

  65. Huang J, Kim-Shapiro DB, King SB. Catalase-mediated nitric oxide formation from hydroxyurea. J Med Chem. 2004;47:3495–501.

    Article  CAS  Google Scholar 

  66. Juul T, Malolepszy A, Dybkær K, Kidmose R, Rasmussen JT, Andersen GR, et al. The in vivo toxicity of hydroxyurea depends on its direct target catalase. J Biol Chem. 2010;285:21411–5.

    Article  CAS  Google Scholar 

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  1. Laboratório de Investigação em Genética e Hematologia Translacional – LIGHT, Instituto Gonçalo Moniz - IGM/FIOCRUZ, Salvador, Brazil

    Sètondji Cocou Modeste Alexandre Yahouédéhou, Caroline Conceição da Guarda, Uche Samuel Ndidi, Suellen Pinheiro Carvalho, Rayra Pereira Santiago, Milena Magalhães Aleluia, Rodrigo Mota de Oliveira & Marilda de Souza Gonçalves

  2. Laboratório de Pesquisa em Anemia – LPA, Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal da Bahia, Salvador, Brazil

    Sètondji Cocou Modeste Alexandre Yahouédéhou, Elisângela Vitória Adorno, Suellen Pinheiro Carvalho, Rodrigo Mota de Oliveira & Marilda de Souza Gonçalves

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Yahouédéhou, S.C.M.A., Adorno, E.V., da Guarda, C.C. et al. Hydroxyurea in the management of sickle cell disease: pharmacogenomics and enzymatic metabolism. Pharmacogenomics J 18, 730–739 (2018). https://doi.org/10.1038/s41397-018-0045-1

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