Bone Marrow Stromal Cells Constitutively Express High Levels of Cytochrome P4501B1 that Metabolize 7,12-Dimethylbenz[a]anthracene

Heidel, Shawn M.; Czuprynski, Charles J.; Jefcoate, Colin R.

doi:10.1124/mol.54.6.1000

Cited by 50 publications

(33 citation statements)

References 25 publications

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“…These early effects on progenitor activities and their dependence on AhR and Cyp1b1 parallel the later decreases in immature lymphocytes and granulocytes that occur after 24 h (Fig. 3) (Heidel et al, 1998;Galvá n et al, 2006). The similar disruption effects on myeloid and lymphoid progenitors and their shared AhR-mediated protection each suggest that disruption may actually be directed to their common progenitors.…”

Section: Discussionmentioning

confidence: 66%

Acute Disruption of Bone Marrow Hematopoiesis by Benzo(a)pyrene Is Selectively Reversed by Aryl Hydrocarbon Receptor-Mediated Processes

N’jai

Larsen²,

Bushkofsky³

et al. 2011

Molecular Pharmacology

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Bone marrow (BM) hematopoietic cells are selectively sensitive to polycyclic aromatic hydrocarbons (PAH) in vivo. 7,12-Dimethylbenz(a)anthracene (DMBA), but not benzo(a)pyrene (BP), depletes BM hematopoietic cells in C57BL/6 mice. This difference is due to a BP-selective aryl hydrocarbon receptor (AhR)-mediated recovery. Colony-forming unit assays show suppression of lymphoid progenitors by each PAH within 6 h but a subsequent recovery, exclusively after BP treatment. Suppression of myeloid progenitors (6 h) occurs only for DMBA. Each progenitor responded equally to DMBA and BP in congenic mice expressing the PAH-resistant AhR (AhR d ). AhR, therefore, mediates this BP recovery in each progenitor type. These PAH suppressions depend on Cyp1b1-mediated metabolism. Paradoxically, few genes responded to DMBA, whereas 12 times more responded to BP. Progenitor suppression by DMBA, therefore, occurs with minimal effects on the general BM population. Standard AhR-mediated stimulations (Cyp1a1, Cyp1b1, Ahrr) were similar for each PAH and for the specific agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin but were absent in AhR d mice. A group of 12 such AhR responses was sustained from 6 to 24 h. A second, larger set of BP responses (chemokines, cytokines, cyclooxygenase 2) differed in two respects; DMBA responses were low and BP responses declined extensively from 6 to 24 h. A third cluster exhibited BP-induced increases in protective genes (Nqo1, GST-mu) that appeared only after 12 h. Conversion of BP to quinones contributes oxidative signaling not seen with DMBA. We propose that genes in this second cluster, which share oxidative signaling and AhR activation, provide the AhR-dependent protection of hematopoietic progenitors seen for BP.

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Section: Discussionmentioning

confidence: 66%

Acute Disruption of Bone Marrow Hematopoiesis by Benzo(a)pyrene Is Selectively Reversed by Aryl Hydrocarbon Receptor-Mediated Processes

N’jai

Larsen²,

Bushkofsky³

et al. 2011

Molecular Pharmacology

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“…Apoptosis does not occur in pre-B (70Z/3) cells incubated with DMBA in the absence of stromal (BMS2) cells. We have demonstrated that CYP1B1 present in bone marrow stromal cells activates DMBA to an immunotoxic metabolite that induces apoptosis in pre-B cells (Heidel et al, 1998). This parallels the DMBA-induced loss of myeloid and lymphoid cells in bone marrow in vivo, which is totally dependent on CYP1B1.…”

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confidence: 81%

7,12-Dimethylbenz[a]anthracene Induces Apoptosis in Murine Pre-B Cells through a Caspase-8–Dependent Pathway

Page

O'Brien

Jefcoate

et al. 2002

Molecular Pharmacology

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Polycyclic aromatic hydrocarbons (PAHs) have been demonstrated to cause a variety of tumors and immunosuppressive effects. Our laboratory, and others, have demonstrated that coculture of progenitor B lymphocytes (pre-B cells) with bone marrow stromal cells and the model PAH 7,12-dimethylbenz[a]anthracene (DMBA) results in pre-B cell apoptosis. In this study we investigated the molecular events that precede apoptosis in DMBA-treated 70Z/3 cells, a pre-B cell line. Using caspase activity assays and immunoblotting techniques, we determined the temporal pattern of caspase expression in the pre-B cells. Using caspase inhibitors, we demonstrated that DMBA-mediated pre-B cell apoptosis is dependent on activation of caspase-8, whereas caspase-9 activation is essential for maximal apoptosis. We also demonstrated that DMBA activated PKR, an interferon-inducible protein kinase, in pre-B cells. PKR in turn can activate caspase-8 independently of death receptor ligation. As a result of these studies, we propose a novel PKR-dependent pathway for activation of apoptosis in DMBA-treated pre-B cells.

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“…Recent reports showed that AHR activation of bone marrow stromal cells was necessary for benz[a]pyrene-or DMBA-induced pre-B-cell apoptosis (7,8,13). In contrast to these reports, Heidel et al showed that the metabolic activation of DMBA in bone marrow stromal cells is required for pre-B-cell apoptosis (35,36). We also examined DMBA-induced lymphoid cytotoxicity using Ah-nonresponsive mice, mEH-null mice and the wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of 7,12-Dimethylbenz[a]anthracene-Induced Immunotoxicity: Role of Metabolic Activation at the Target Organ

Miyata

Furukawa

Takahashi

et al. 2001

Japanese Journal of Pharmacology

118

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ABSTRACT-The polycyclic aromatic hydrocarbon, 7,12-dimethylbenz [a]anthracene (DMBA), is an immunosuppressor as well as a potent organ-specific carcinogen. To understand the organ-specific mechanism of DMBA-induced lymphoid toxicity, aryl hydrocarbon-nonresponsive mice and microsomal epoxide hydrolase (mEH)-null mice were analyzed. DMBA caused a dose-dependent decrease in spleen weights, but not the thymus weights in aryl hydrocarbon-nonresponsive mice. On the other hand, both spleen and thymus weights were decreased to less than a half in wild-type mice exposed to 30 mg/kg of DMBA. In contrast, no decrease was detected in spleen weights of mEH-null mice exposed to up to 100 mg/ kg of DMBA, while thymus weights were markedly lower. Responses to the B-cell mitogen lipopolysaccharide and to T-cell mitogen phytohemagglutinin were nearly completely abolished in splenocytes isolated from wild-type mice treated with 100 mg/kg of DMBA. These responses were decreased, but maintained in splenocytes isolated from mEH-null mice treated with DMBA. Two DMBA metabolites dependent on mEH including DMBA-3,4-diol were detected in an HPLC chromatogram of spleen microsomes isolated from wild-type mice, but not those from mEH-null mice. These results suggest the involvement of mEH in splenic activation of DMBA for immunotoxicity and the difference for the DMBA-induced lymphoid toxicity between spleen and thymus.

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Bone Marrow Stromal Cells Constitutively Express High Levels of Cytochrome P4501B1 that Metabolize 7,12-Dimethylbenz[a]anthracene

Cited by 50 publications

References 25 publications

Acute Disruption of Bone Marrow Hematopoiesis by Benzo(a)pyrene Is Selectively Reversed by Aryl Hydrocarbon Receptor-Mediated Processes

Acute Disruption of Bone Marrow Hematopoiesis by Benzo(a)pyrene Is Selectively Reversed by Aryl Hydrocarbon Receptor-Mediated Processes

7,12-Dimethylbenz[a]anthracene Induces Apoptosis in Murine Pre-B Cells through a Caspase-8–Dependent Pathway

Mechanism of 7,12-Dimethylbenz[a]anthracene-Induced Immunotoxicity: Role of Metabolic Activation at the Target Organ

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