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Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies

The Pharmacogenomics Journal volume 15, pages 405–413 (2015)Cite this article

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Abstract

The role of cytochrome P450 2J2 (CYP2J2) in cyclophosphamide (Cy) bioactivation was investigated in patients, cells and microsomes. Gene expression analysis showed that CYP2J2 mRNA expression was significantly (P<0.01) higher in 20 patients with hematological malignancies compared with healthy controls. CYP2J2 expression showed significant upregulation (P<0.05) during Cy treatment before stem cell transplantation. Cy bioactivation was significantly correlated to CYP2J2 expression. Studies in HL-60 cells expressing CYP2J2 showed reduced cell viability when incubated with Cy (half maximal inhibitory concentration=3.6 mM). Inhibition of CYP2J2 using telmisartan reduced Cy bioactivation by 50% and improved cell survival. Cy incubated with recombinant CYP2J2 microsomes has resulted in apparent Km and Vmax values of 3.7–6.6 mM and 2.9–10.3 pmol/(min·pmol) CYP, respectively. This is the first study demonstrating that CYP2J2 is equally important to CYP2B6 in Cy metabolism. The heart, intestine and urinary bladder express high levels of CYP2J2; local Cy bioactivation may explain Cy-treatment-related toxicities in these organs.

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Acknowledgements

The present study was supported by grants from the Swedish Cancer Society (Cancerfonden) and the Swedish Childhood Cancer Foundation (Barncancerfonden).

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Author notes

  1. P Afsharian

    Present address: 5Current address: Pharmacogenetics Group, Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.,

  2. Y Terelius and Z Potácová: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Laboratory Medicine, Experimental Cancer Medicine (ECM), Clinical Research Centre, Karolinska Institutet, Stockholm, Sweden

    I El-Serafi, M Fares, M Abedi-Valugerdi, P Afsharian, Z Potácová & M Hassan

  2. Department of Oncology-Pathology, Cancer Center of Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden

    A Moshfegh

  3. Department of Discovery Research, Medivir AB, Stockholm, Sweden

    Y Terelius

  4. Clinical Research Center (KFC), Novum, Karolinska University Hospital-Huddinge, Stockholm, Sweden

    Z Potácová & M Hassan

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Correspondence to M Hassan.

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El-Serafi, I., Fares, M., Abedi-Valugerdi, M. et al. Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies. Pharmacogenomics J 15, 405–413 (2015). https://doi.org/10.1038/tpj.2014.82

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