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MTHFR C677T/A1298C genotype: a possible risk factor for liver sinusoidal obstruction syndrome

Bone Marrow Transplantation volume 49, pages 726–727 (2014)Cite this article

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High-dose BU has become a mainstay in conditioning regimens for hematopoietic SCT (HSCT), despite its narrow therapeutic window and high toxicity. BU areas under the concentration time curves (AUC) higher than 1500 μM min are associated with increased risk of liver sinusoidal obstruction syndrome (SOS),1 which still contributes to significant treatment-related morbidity and mortality. Therapeutic and toxic responses to BU are largely unpredictable, and occur in patients receiving identical treatment schedules. An AUC of 900–1500 μM min has been defined as the target exposure range in adults,1 and controlling patient AUC by therapeutic drug monitoring (TDM) has become mandatory in many transplant centers, especially with oral administration of BU.2 Despite TDM, SOS still presents a serious challenge in HSCT, suggesting other predisposing factors to liver toxicity likely exist in patients who develop this complication.

BU, like many chemotherapeutic drugs associated with liver toxicity, is metabolized in the liver via conjugation of glutathione by members of the glutathione S transferase (GST) family of phase II detoxification enzymes.3 Srivastava et al.4 assessed the impact of polymorphisms in GST genes on the risk of SOS in patients with β-thalassemia major undergoing HSCT and concluded that the GSTM1-null genotype predisposes to SOS. We did not find this association in thalassemic children of Israeli descent.5

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References

  1. Slattery JT, Sanders JE, Buckner CD, Schaffer RL, Lambert KW, Langer FP et al. Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transplant 1995; 16: 31–42.

    CAS  PubMed  Google Scholar 

  2. McCune JS, Holmberg LA . Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol 2009; 5: 957–969.

    Article  CAS  PubMed  Google Scholar 

  3. Goekkurt E, Stoehlmacher J, Stueber C, Wolschke C, Eiermann T, Iacobelli S et al. Pharmacogenetic analysis of liver toxicity after busulfan/cyclophosphamide-based allogeneic hematopoietic stem cell transplantation. Anticancer Res 2007; 27: 4377–4380.

    CAS  PubMed  Google Scholar 

  4. Srivastava A, Poonkuzhali B, Shaji RV, George B, Mathews V, Chandy M et al. Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood 2004; 104: 1574–1577.

    Article  CAS  PubMed  Google Scholar 

  5. Elhasid R, Krivoy N, Rowe JM, Sprecher E, Adler L, Elkin H et al. Influence of glutathione S-transferase A1, P1, M1, T1 polymorphisms on oral busulfan pharmacokinetics in children with congenital hemoglobinopathies undergoing hematopoietic stem cell transplantation. Pediatr Blood Cancer 2010; 55: 1172–1179.

    Article  PubMed  Google Scholar 

  6. Friedman G, Goldschmidt N, Friedlander Y, Ben-Yehuda A, Selhub J, Babaey S et al. A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr 1999; 129: 1656–1661.

    Article  CAS  PubMed  Google Scholar 

  7. Vitvitsky V, Mosharov E, Tritt M, Ataullakhanov F, Banerjee R . Redox regulation of homocysteine-dependent glutathione synthesis. Redox Rep 2003; 8: 57–63.

    Article  CAS  PubMed  Google Scholar 

  8. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED . Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 1984; 4: 116–122.

    Article  CAS  PubMed  Google Scholar 

  9. Krivoy N, Zuckerman T, Elkin H, Froymovich L, Rowe JM, Efrati E . Pharmacokinetic and pharmacogenetic analysis of oral busulfan in stem cell transplantation: prediction of poor drug metabolism to prevent drug toxicity. Curr Drug Safety 2012; 7: 211–217.

    Article  CAS  Google Scholar 

  10. Song JH, Kim HJ, Lee CH, Kim SJ, Hwang SY, Kim TS . Identification of gene expression signatures for molecular classification in human leukemia cells. Int J Oncol 2006; 29: 57–64.

    CAS  PubMed  Google Scholar 

  11. DeLeve LD, Wang X . Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes. Pharmacology 2000; 60: 143–154.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was funded by the Israel Ministry of Health, Chief Scientist Grant (number 3-00000-6030).

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Authors and Affiliations

  1. Rappaport-Rambam Center for Translational Genetics, B. Rappaport Institute for Research in the Medical Sciences and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    E Efrati, E Ben-Ami & N Krivoy

  2. Clinical Pharmacology Institute, Haifa, Israel

    E Efrati & N Krivoy

  3. Rambam Health Care Campus, Hematology Institute, Haifa, Israel

    T Zuckerman

  4. Technion-Israel Institute of Technology, B. Rappaport Faculty of Medicine, Haifa, Israel

    T Zuckerman & N Krivoy

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  1. E Efrati
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Correspondence to E Efrati.

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Efrati, E., Zuckerman, T., Ben-Ami, E. et al. MTHFR C677T/A1298C genotype: a possible risk factor for liver sinusoidal obstruction syndrome. Bone Marrow Transplant 49, 726–727 (2014). https://doi.org/10.1038/bmt.2014.16

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