Comparative Effect of Heme Analogues on Hematopoiesis in Lymphoproliferative Disorders

Lutton, John D.; Chertkov, J. L.; Levere, Richard D.; Abraham, Nader G.

doi:10.3109/10428199109068123

Cited by 11 publications

(14 citation statements)

References 15 publications

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“…Effect of Metalloporphyrins on Human Bone Marrow Growth. We have previously shown that heme enhances in vitro erythropoiesis (1,15). We therefore examined the dose effects of ZnPP and SnPP on human bone marrow erythroid colony growth (CFU-E, BFU-E).…”

Section: Resultsmentioning

confidence: 99%

“…Heme analogues were obtained from Porphyrin Products (Logan, UT) and included tin mesoporphyrin (SnMP), tin protoporphyrin (SnPP), zinc mesoporphyrin (ZnMP), ZnPP, CrMP, protoporphyrin IX (PPIX), mesoporphyrin IX (MPIX), and heme. The heme analogues, except for ZnMP and ZnPP, were prepared and added to cultures as described (1). Zinc porphyrins were first dissolved in propylene glycol to give a final concentration of 10% (vol͞vol) and then prepared as described (1).…”

Section: Preparation Of Cellsmentioning

confidence: 99%

“…The heme analogues, except for ZnMP and ZnPP, were prepared and added to cultures as described (1). Zinc porphyrins were first dissolved in propylene glycol to give a final concentration of 10% (vol͞vol) and then prepared as described (1).…”

Section: Preparation Of Cellsmentioning

confidence: 99%

“…Heme, a potent inducer of HO expression has been shown to have modulatory effects on hematopoiesis (1). A comprehensive study comparing the effects on hematopoietic cells of synthetic heme analogues, which inhibit HO activity has, not previously been undertaken.…”

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confidence: 99%

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Zinc porphyrins: Potent inhibitors of hematopoieses in animal and human bone marrow

Lutton

Abraham

Drummond

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The effects of selected heme analogues on heme oxygenase activity in tissues and on human and rabbit bone marrow hematopoietic colony growth were examined. Zinc protoporphyrin (ZnPP) and zinc mesoporphyrin (ZnMP), at concentrations ranging between 1 and 20 M, produced significant inhibition of human and rabbit bone marrow erythroid (CFU-E, BFU-E) and myeloid (CFU-GM) colony growth. The growth inhibition produced by ZnPP or ZnMP was not overcome with exposure of cultures to elevated levels of the growth factors erythropoietin and granulocytemacrophage colony stimulating factor. In contrast, tin protoporphyrin and tin mesoporphyrin did not display any significant bone marrow toxicity when used at similar concentrations. In other studies, differential effects of tin mesoporphyrin and ZnMP administered intravenously on kidney heme oxygenase were demonstrated. Chromium mesoporphyrin administered intravenously proved lethal to animals. These results indicate that exposure of bone marrow to ZnPP and ZnMP can be deleterious to hematopoietic cells and raise the possibility that ZnPP, which is endogenously formed and found in high concentration in red blood cells in lead-poisoned children, may itself participate in the bone marrow toxicity produced by this metal.Hematopoietic cell growth and differentiation within the bone marrow microenvironment are dependent on a complex interplay of cells, cytokines, growth factors, and heme oxygenase (HO) activity, with the latter enzyme playing a major regulatory role in this system. Heme, a potent inducer of HO expression has been shown to have modulatory effects on hematopoiesis (1). A comprehensive study comparing the effects on hematopoietic cells of synthetic heme analogues, which inhibit HO activity has, not previously been undertaken. Information from this type of study is of special importance because of the clinical potential (2-8) of certain of these compounds.In this study we compared the effects of tin and zinc porphyrins on hematopoietic cell growth and colony formation in animal and human bone marrow cultures. Such cell systems are especially vulnerable to the nature of their microenvironment and thus can provide sensitive indices of the deleterious potential of various chemical agents.The results of this study indicate that zinc porphyrins are toxic to both myeloid and erythroid cell growth even at low concentrations. In contrast, tin porphyrins, even at high concentrations, displayed no toxic effects on hematopoiesis. In other experiments tin and zinc porphyrins were shown to have differing effects on renal HO activity when administered intravenously (i.v.). Chromium mesoporphyrin (CrMP) proved lethal to animals when administered by the iv route.These findings provide additional examples of the differential effects of HO inhibitors on cell functions based on their central metal atom and on their route of administration. The inhibitory actions of zinc porphyrins on bone marrow cell growth represent newly identified deleterious properties of these metalloporphyr...

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Section: Resultsmentioning

confidence: 99%

Section: Preparation Of Cellsmentioning

confidence: 99%

Section: Preparation Of Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Zinc porphyrins: Potent inhibitors of hematopoieses in animal and human bone marrow

Lutton

Abraham

Drummond

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, heme and certain other metalloporphyrins stimulate the immune system and enhance erythropoiesis (4,5). Heme, as well as the synthetic heme analog tin protoporphyrin, significantly enhances bone marrow erythroid progenitor proliferation and differentiation in lymphoproliferative disorders (6). It has also been shown that heme and other synthetic heme analogs significantly inhibit HIV-1 RT activity in a noncompetitive manner with respect to deoxythymidine triphosphate and markedly enhance the inhibitory effect of AZT-TP on HIV-1 RT (7).…”

mentioning

confidence: 99%

The Connection Domain Is Implicated in Metalloporphyrin Binding and Inhibition of HIV Reverse Transcriptase

Argyris

Vanderkooi

Venkateswaran

et al. 1999

Journal of Biological Chemistry

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We have shown that heme and zinc protoporphyrin inhibit both human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) reverse transcriptases (RTs) and, in combination with other nucleoside and non-nucleoside inhibitors, exert an additive effect on HIV-1 RT inhibition. Screening of a phage peptide library against heme resulted in the isolation of a peptide with sequence similarity to sequence 398 -407 from the connection subdomain of both HIV-1 and HIV-2 RTs, suggesting that this highly conserved region of HIV RTs corresponds to the binding site for metalloporphyrins and a new site for inhibition of enzyme activity. Inclusion of a synthetic peptide corresponding to the exact sequence 398 -407 of HIV-1 RT in RT inhibition assays had a protective effect on metalloporphyrin inhibition, as it was able to reverse the inhibitory effect of both metalloporphyrins on HIV-1 RT activity. Furthermore, intrinsic fluorescence assays indicated that these metalloporphyrins bind to synthetic peptide 398 -407 as well as to intact dimeric HIV-1 RT. The identification of this novel inhibition site will help to expand our understanding of the mode of action of metalloporphyrins in RT inhibition and will assist in the design and development of more potent metalloporphyrin RT inhibitors for the management of HIV infection.

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New Concepts in Bilirubin and Jaundice: Report of the Third International Bilirubin Workshop, April 6–8, 1995, Trieste, Italy

Tiribelli

Ostrow

1996

Hepatology

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only partial and temporary relief of hyperbilirubinemia; tocytic transporters of UCB and related organic anions extracorporeal liver assist devices have had some sucwere described. Special emphasis was given to the adencess in initial human studies; and inhibition of heme osine triphosphate (ATP)-dependent canalicular multioxygenase (HO) with metalloporphyrins, especially tin specific organic anion transporter that is defective in mesoporphyrin, which markedly decreases bilirubin production for prolonged periods, is a new alternative dipyrrole (Fig. 1). In solution, however, this structure is flexi- Received October 3, 1995; accepted June 6, 1996. ble, and small changes ({40Њ) in the interplanar angle (u)

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Comparative Effect of Heme Analogues on Hematopoiesis in Lymphoproliferative Disorders

Cited by 11 publications

References 15 publications

Zinc porphyrins: Potent inhibitors of hematopoieses in animal and human bone marrow

Zinc porphyrins: Potent inhibitors of hematopoieses in animal and human bone marrow

The Connection Domain Is Implicated in Metalloporphyrin Binding and Inhibition of HIV Reverse Transcriptase

New Concepts in Bilirubin and Jaundice: Report of the Third International Bilirubin Workshop, April 6–8, 1995, Trieste, Italy

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