Demonstration of mRNA for five species of cytochrome P450 in human bone marrow, bone marrow‐derived macrophages and human haemopoietic cell lines

Hodges, Vivien M.; Molloy, Gael; Wickramasinghe, Sunitha N.

doi:10.1046/j.1365-2141.2000.01816.x

Cited by 29 publications

(22 citation statements)

References 45 publications

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“…Although it was not evident whether a cytochrome P450 pathway could synthesize the metabolite EXP3179 in THP-1 macrophages, the expression of cytochrome P450 isoenzymes, 2C9 and 3A4, which are linked to losartan metabolism, is well defined in the lineage of monocytes/macrophages. 22,23 Alternatively, it was reported that losartan itself could serve as a PPARg agonist, 12 supporting the idea that losartan attenuates LPS-induced proinflammatory gene expression by acting as a PPARg agonist. In this study, we did not use other AT1R blockers with strong PPARg activity, such as telmisartan and irbesartan, or PPARg agonists, such as glitazone, to demonstrate the involvement of the PPARg pathway because we wanted to clarify the interaction between RAS and TLR-signaling pathways in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

Nakajima

Kuba

et al. 2010

Hypertens Res

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Macrophages have critical roles in the pathogenesis of atherosclerosis by activating the innate immune system and producing inflammatory cytokines. Accumulating evidence indicates that angiotensin type 1 receptor (AT1R) blockers exert antiinflammatory effects in inflammatory diseases including atherosclerosis. In this study, we investigated the effect of losartan, an AT1R blocker, on the proinflammatory gene expression induced by bacterial lipopolysaccharide (LPS) in a well-defined in vitro human THP-1 macrophage system. We found that losartan significantly attenuated the LPS-induced expression of proinflammatory genes TNF-a, IL-8 and COX-2. However, exogenous angiotensin II (AngII) had no effect on LPS-induced inflammatory signaling despite the expression of AT1R. In addition, losartan did not block LPS-induced IjB phosphorylation, which is downstream of Toll-like receptor activation. Peroxisome proliferator-activated receptor-gamma (PPARc) antagonists, GW9662 and T0070907, reversed the inhibitory effects of losartan on LPS-induced TNF-a and IL-8 expression in THP-1 macrophages. These observations suggest that losartan inhibits LPS-induced proinflammatory gene expression in macrophages by activating the PPARc pathway rather than by the competitive inhibition of AT1R binding to AngII.

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Section: Discussionmentioning

confidence: 99%

Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

Nakajima

Kuba

et al. 2010

Hypertens Res

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“…The presence of P450 2E1 in bone marrow has been implicated by Bernauer et al [15]. Hodges et al [13] found five P450s, including P450 1A1, 2A6/7, 2D6, 2E1, and 3A4 in bone marrow, in macrophages, and in hematopoietic cell lines. Nguyen et al [14] found even more P450 forms (16) in mononuclear fraction of peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

“…The information about expression of genes coding for biotransformation enzymes, especially P450s in population of CD34 + human hematopoietic stem and progenitor cells, is still limited. To date, expression of mRNA for five cytochrome P450s (CYP1A1, 2A6/7, 2D6, 2E1, and 3A4) was demonstrated in human bone marrow, in various types of macrophages, in cell lines HL-60 and HEL, and in Epstein-Barr virus-transformed B-lymphoblastoid cell lines as well as in mononuclear cells [13,14]. Presence of P450 2E1 in bone marrow cells was indicated by Western blotting [15].…”

Section: Cytochrome P450 In Stem Cellsmentioning

confidence: 99%

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

et al. 2005

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Expression of major cytochrome P450 forms (P450) was followed in preparation of purified hematopoietic CD34 + stem and progenitor cells. Levels of transcripts as well as mature proteins were traced by quantitative real-time polymerase chain reaction and by Northern and Western blotting. P450 1B1 and P450 2E1 proteins and respective mRNAs were found in all cases. On the other hand, no expression of P450 3A4, P450 3A7, and P450 2C9 was found. The results showed that expression of various P450 enzymes starts at different stages of cell differentiation. Both P450 forms found are known to be connected with cancer cells and with activation of procarcinogens (P450 1B1, polycyclic aromatic hydrocarbons; P450 2E1, nitrosamines, and solvents). Hence, cells at the early stage of differentiation already may be influenced by interaction with xenobiotics. This fact should also be taken into consideration when hematopoietic cell transplant therapy is applied.

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“…Consequently, the content of tissue-specific P450 isoforms may represent an important parameter determining both the therapeutic efficacy and susceptibility to the toxic effects of administered xenobiotics. In this regard, lymphatic tissue from spleen, thymus and bone marrow have been reported to express, albeit at considerably lower levels than observed in liver, isoforms from the CYP1A, CYP2A, CYP2B, CYP2E and/or CYP2J subfamilies [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Sex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone

Thangavel

Dhir

Volgin

et al. 2007

Biochemical Pharmacology

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CYP2C11, the most commonly expressed isoform of cytochrome P450 in male rat liver, was measured in spleen, thymus and bone marrow by quantitative real-time PCR and enhanced Western blotting. CYP2C11 concentrations in the lymphoid tissues were a fraction of that observed in liver, but like the liver, were sexually dimorphic (M>F) with mRNA and protein levels in agreement. Although the response to hypophysectomy varied according to tissue and sex, expression levels of CYP2C11 in all measured tissues remained greater in males. Further differences in CYP2C11 expression between liver and lymphoid tissue were observed following restoration of the circulating masculine growth hormone profile in hypophysectomized rats. In contrast to the liver where the renaturalized growth hormone profile elevated CYP2C11 expression in both sexes, the response was opposite in spleen and thymus with isoform concentrations declining in both sexes. Lastly, the divergent response of CYP2C11 between the liver and immune system was examined in cultured splenocytes exposed to different mitogens. In contrast to the dramatic depletion of CYP2C11 reported in proliferating hepatocytes, mitogen-stimulation resulted in a significant elevation in splenocyte CYP2C11 expression. In summary, we report for the first time that thymus, spleen and bone marrow express, albeit nominal, sex-dependent levels of CYP2C11 (M>F) whose regulation appears to be under some hormonal control, but very different from that of the hepatic isoform.

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Demonstration of mRNA for five species of cytochrome P450 in human bone marrow, bone marrow‐derived macrophages and human haemopoietic cell lines

Cited by 29 publications

References 45 publications

Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

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

Sex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone

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Demonstration of mRNA for five species of cytochrome P450 in human bone marrow, bone marrow‐derived macrophages and human haemopoietic cell lines

Cited by 29 publications

References 45 publications

Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

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

Sex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone

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