title: Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies.
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.
authors.affiliation: Experimental Cancer Medicine (ECM), Clinical Research Centre, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: El-Serafi
authors.affiliation: Experimental Cancer Medicine (ECM), Clinical Research Centre, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Fares
authors.affiliation: Experimental Cancer Medicine (ECM), Clinical Research Centre, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Abedi-Valugerdi
authors.affiliation: Experimental Cancer Medicine (ECM), Clinical Research Centre, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Afsharian
authors.affiliation: Cancer Center of Karolinska (CCK), Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Moshfegh
authors.affiliation: Department of Discovery Research, Medivir AB, Stockholm, Sweden.
authors.forename: Y
authors.initials: Y
authors.lastname: Terelius
authors.affiliation: Experimental Cancer Medicine (ECM), Clinical Research Centre, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.|Clinical Research Center (KFC), Novum, Karolinska University Hospital-Huddinge, Stockholm, Sweden.
authors.forename: Z
authors.initials: Z
authors.lastname: Potácová
authors.affiliation: Experimental Cancer Medicine (ECM), Clinical Research Centre, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.|Clinical Research Center (KFC), Novum, Karolinska University Hospital-Huddinge, Stockholm, Sweden.
authors.forename: M
authors.identifier: http://orcid.org/0000-0003-1927-5859
authors.initials: M
authors.lastname: Hassan
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006321:Heart / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D033581:Stem Cell Transplantation; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C000717350:CYP2J2 protein, human; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2