Expression of Cytochrome P450 Genes in CD34
            <sup>+</sup>
            Hematopoietic Stem and Progenitor Cells

Souček, Pavel; Anzenbacher, Pavel; Skoumalova, Ivana; Dvořák, Michal

doi:10.1634/stemcells.2005-0066

Cited by 39 publications

(23 citation statements)

References 19 publications

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“…Recent study demonstrated the expression of several CYP genes in the CD34 ϩ hematopoietic stem cells. 23) Together with our data, it is possible that the cells at the early stage of hematopoietic differentiation may be influenced by interaction with xenobiotics, depending on the extents of CYP expresstion.…”

Section: Discussionsupporting

confidence: 68%

Changes in the Expression of Cytochrome P450 Genes in Hemin-Induced Differentiated K562 Cells

Nagai

Shimizu

Sakamoto

et al. 2007

Biological & Pharmaceutical Bulletin

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We have previously reported the expression of CYP genes in human myeloblastic and lymphoid cell lines, and the induction of the CYP3A4 and GSTP1 genes by oxidative stress in the human erythroleukemia cell line, K562. To further elucidate the role of drug metabolizing enzymes in hematogenesis, we have characterized the expression of CYP genes in hemin-induced differentiated K562 cells. After incubation with 50 m mM hemin for 3 d, the expression of CYP1A1 and CYP3A4 genes was induced by 2.5-and 3.5-fold, respectively. In contrast, the CYP1B1 and CYP2E1 genes were downregulated in these cells to below 10% of the control levels. Moreover, these changes correlated with the hemin dose and culture time. Metabolism of midazolam, a probe substrate for CYP3A4, in the differentiated K562 cells increased by 2-folds, suggesting that the induction of CYP3A4 activity is consistent with the mRNA level. If these changes in the CYP expression profile in hematopoietic cells occurred, the susceptibility to xenobiotics and/or the therapeutic drugs of the cells might be influenced, and it also affects the metabolism of endogenous substrates, such as steroids and prostaglandins.

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Section: Discussionsupporting

confidence: 68%

Changes in the Expression of Cytochrome P450 Genes in Hemin-Induced Differentiated K562 Cells

Nagai

Shimizu

Sakamoto

et al. 2007

Biological & Pharmaceutical Bulletin

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“…Various results have shown that hematopoietic stem and progenitor cells express high levels of ABC transporters [72,73] as well as CYP1B1 [74]. Indeed, strong expression of CYP1B1 mRNA and protein have been found in purified hematopoietic CD34 þ undifferentiated cells from two patients' peripheral blood [74]. These latter results underline that imatinib metabolism should also be considered in these undifferentiated cells.…”

Section: Discussionmentioning

confidence: 88%

“…Moreover, imatinib efficacy appears to be reduced in stem and progenitor cancer cells [69][70][71] and their survival (quiescent cells) seems to be the starting point for the emergence of resistant cell clones and treatment relapse [71]. Various results have shown that hematopoietic stem and progenitor cells express high levels of ABC transporters [72,73] as well as CYP1B1 [74]. Indeed, strong expression of CYP1B1 mRNA and protein have been found in purified hematopoietic CD34 þ undifferentiated cells from two patients' peripheral blood [74].…”

Section: Discussionmentioning

confidence: 99%

In vitro biotransformation of imatinib by the tumor expressed CYP1A1 and CYP1B1

Rochat

Zoete

Grosdidier

et al. 2008

Biopharm & Drug Disp

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The main objective of the study was to examine the biotransformation of the anticancer drug imatinib in target cells by incubating it with oxidoreductases expressed in tumor cells. The second objective was to obtain an in silico prediction of the potential activity of imatinib metabolites. An in vitro enzyme kinetic study was performed with cDNA expressed human oxidoreductases and LC-MS/MS analysis. The kinetic parameters (Km and Vmax) were determined for six metabolites. A molecular modeling approach was used to dock these metabolites to the target Abl or Bcr-Abl kinases. CYP3A4 isozyme showed the broadest metabolic capacity, whereas CYP1A1, CYP1B1 and FMO3 isozymes biotransformed imatinib with a high intrinsic clearance. The predicted binding modes for the metabolites to Abl were comparable to that of the parent drug, suggesting potential activity. These findings indicate that CYP1A1 and CYP1B1, which are known to be overexpressed in a wide range of tumors, are involved in the biotransformation of imatinib. They could play a role in imatinib disposition in the targeted stem, progenitor and differentiated cancer cells, with a possible contribution of the metabolites toward the activity of the drug.

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“…1A, f). Although cyanide and SA are not highly specific inhibitors of MPO but rather block hemecontaining enzymes and total heme synthesis, respectively, together, these results strongly suggest that H 2 O 2 -dependent MPO catalysis is involved in the generation of etoposide-O ⅐ radicals, especially because MPO is a major heme-containing protein in growth factor-mobilized CD34 ϩ cells and there is little expression of cytochromes P450 in CD34 ϩ cells capable of etoposide oxidation (Soucek et al, 2005).…”

Section: Detection Of the Etoposide-o ⅐ In Intact Cd34mentioning

confidence: 88%

Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34⁺Cells

Vlasova¹,

Wei²,

Goff³

et al. 2010

Mol Pharmacol

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Etoposide is a widely used anticancer drug successfully used for the treatment of many types of cancer in children and adults. Its use, however, is associated with an increased risk of development of secondary acute myelogenous leukemia involving the mixed-lineage leukemia (MLL) gene (11q23) translocations. Previous studies demonstrated that the phenoxyl radical of etoposide can be produced by action of myeloperoxidase (MPO), an enzyme found in developing myeloid progenitor cells, the likely origin for myeloid leukemias. We hypothesized, therefore, that one-electron oxidation of etoposide by MPO to its phenoxyl radical is important for converting this anticancer drug to genotoxic and carcinogenic species in human CD34ϩ myeloid progenitor cells. In the present study, using electron paramagnetic resonance spectroscopy, we provide conclusive evidence for MPO-dependent formation of etoposide phenoxyl radicals in growth factor-mobilized CD34 ϩ cells isolated from human umbilical cord blood and demonstrate that MPO-induced oxidation of etoposide is amplified in the presence of phenol. Formation of etoposide radicals resulted in the oxidation of endogenous thiols, thus providing evidence for etoposide-mediated MPO-catalyzed redox cycling that may play a role in enhanced etoposide genotoxicity. In separate studies, etoposide-induced DNA damage and MLL gene rearrangements were demonstrated to be dependent in part on MPO activity in CD34 ϩ cells. Together, our results are consistent with the idea that MPO-dependent oxidation of etoposide in human hematopoietic CD34 ϩ cells makes these cells especially prone to the induction of etoposide-related acute myeloid leukemia.

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Expression of Cytochrome P450 Genes in CD34 ⁺ Hematopoietic Stem and Progenitor Cells

Cited by 39 publications

References 19 publications

Changes in the Expression of Cytochrome P450 Genes in Hemin-Induced Differentiated K562 Cells

Changes in the Expression of Cytochrome P450 Genes in Hemin-Induced Differentiated K562 Cells

In vitro biotransformation of imatinib by the tumor expressed CYP1A1 and CYP1B1

Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34⁺Cells

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Expression of Cytochrome P450 Genes in CD34 + Hematopoietic Stem and Progenitor Cells

Cited by 39 publications

References 19 publications

Changes in the Expression of Cytochrome P450 Genes in Hemin-Induced Differentiated K562 Cells

Changes in the Expression of Cytochrome P450 Genes in Hemin-Induced Differentiated K562 Cells

In vitro biotransformation of imatinib by the tumor expressed CYP1A1 and CYP1B1

Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34+Cells

Contact Info

Product

Resources

About

Expression of Cytochrome P450 Genes in CD34 ⁺ Hematopoietic Stem and Progenitor Cells

Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34⁺Cells