Modulation of erythropoiesis by novel human bone marrow cytochrome P450-deoendent metabolites of arachidonic acid

Nader G. Abraham, Eric Feldman, J R Falck, John D. Lutton, Michel Laniado Schwartzman

Research output: Contribution to journalArticle

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Abstract

In the hematopoietic system the adherent stromal cells produce cytokines necessary for proliferation and differentiation of hematopoietic cells. In the present study, we showed the ability of adherent stromal cells to generate novel metabolites of arachidonic acid via the NADPH-cytochrome P450-dependent monooxygenase system. These metabolites were recovered in the incubation media, suggesting their release from cells. The formation of arachidonic acid metabolites was inhibited by 7-ethoxyresorufin and SKF-525A, but not by indomethacin or BW-755C. By using two-step highpressure liquid chromatography (HPLC), bone marrowadherent stromal cells and incubation media showed the presence of metabolites in a peak eluted at 19 to 20 minutes. The isolated HPLC peak was used to measure its effect on colony-forming unit-erythroid (CFU-E) growth and compare it with that of synthetic cytochrome P450 arachidonate metabolites, 19- and 20-hydroxyeicosatetraenoic (HETE) acid. These bone marrow cytochrome P450 arachidonic acid metabolites at picomolar concentration potentiated erythropoietin (Epo)-induced CFU-E growth by fourfold to sixfold. Addition of 19- and 20-HETE to the bone marrow culture resulted in a potentiating effect on CFU-E number in a dose-dependent manner. 20-HETE was much more potent in stimulating CFU-E growth than 19-HETE at a similar concentration of 10-11 mol/L. The potentiating effect of 20-HETE resulted in a shifting to the left of the dose-response curve to Epo. To substantiate the finding of an active NADPH-dependent cytochrome P450-metabolizing system, we further examined the ability of adherent cells to metabolize exogenous pharmacologic compounds such as benzo(a)pyrene, a substrate for the heme-cytochrome P450 system, aryl hydrocarbon hydroxylase. The adherent stromal cytochrome P450 metabolizes benzo(a)pyrene at comparable levels to blood vessel endothelial cells. These novel observations underscore the importance of adherent stromal cytochrome P450 to metabolize endogenous substrates, including arachidonic acid, to compounds that may interact in a paracrine manner with Epodependent hematopoietic cells.

Original languageEnglish (US)
Pages (from-to)1461-1466
Number of pages6
JournalBlood
Volume78
Issue number6
StatePublished - Sep 15 1991

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Erythropoiesis
Metabolites
Arachidonic Acid
Cytochrome P-450 Enzyme System
Bone
Bone Marrow
Modulation
Erythroid Precursor Cells
Stromal Cells
Benzo(a)pyrene
Liquid chromatography
Erythropoietin
NADP
Liquid Chromatography
Growth
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine
Proadifen
Aryl Hydrocarbon Hydroxylases
Hematopoietic System
Endothelial cells

ASJC Scopus subject areas

  • Hematology

Cite this

Abraham, N. G., Feldman, E., Falck, J. R., Lutton, J. D., & Schwartzman, M. L. (1991). Modulation of erythropoiesis by novel human bone marrow cytochrome P450-deoendent metabolites of arachidonic acid. Blood, 78(6), 1461-1466.

Modulation of erythropoiesis by novel human bone marrow cytochrome P450-deoendent metabolites of arachidonic acid. / Abraham, Nader G.; Feldman, Eric; Falck, J R; Lutton, John D.; Schwartzman, Michel Laniado.

In: Blood, Vol. 78, No. 6, 15.09.1991, p. 1461-1466.

Research output: Contribution to journalArticle

Abraham, NG, Feldman, E, Falck, JR, Lutton, JD & Schwartzman, ML 1991, 'Modulation of erythropoiesis by novel human bone marrow cytochrome P450-deoendent metabolites of arachidonic acid', Blood, vol. 78, no. 6, pp. 1461-1466.
Abraham, Nader G. ; Feldman, Eric ; Falck, J R ; Lutton, John D. ; Schwartzman, Michel Laniado. / Modulation of erythropoiesis by novel human bone marrow cytochrome P450-deoendent metabolites of arachidonic acid. In: Blood. 1991 ; Vol. 78, No. 6. pp. 1461-1466.
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