The Inhibitory Effect of Heme on Heme Formation In Vivo: Possible Mechanism for the Regulation of Hemoglobin Synthesis*

Gallo, Robert C.

doi:10.1172/jci105505

Cited by 9 publications

(9 citation statements)

References 20 publications

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“…Assimilation of iron, formation of heme de novo, and protein synthesis in these cells are interrelated processes subject to control by the availability of endogenous heme. In whole animals and intact reticulocytes, hemin profoundly inhibits receptor-mediated iron uptake from plasma transferrin by an unknown mechanism (1,2). Under conditions of suboptimal or inhibited protein synthesis, rising concentrations of endogenous free heme probably account for the progressive decline in the rate of iron uptake by reticulocytes (2,3).…”

Section: Gm) Reduced Iron Transport But Increased Cell-associated Tramentioning

confidence: 99%

Hemin inhibits internalization of transferrin by reticulocytes and promotes phosphorylation of the membrane transferrin receptor.

Cox¹,

O'Donnell²,

Aisen³

et al. 1985

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

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Addition of hemin to reticulocytes inhibits incorporation of iron from transferrin [Ponka, P. & Neuwirt, J. (1969) Blood 33,. Heme also regulates protein synthesis in immature erythroid cells through its effects on phosphorylation of the initiation factor eIF-2. We have therefore examined its effects on endocytosis of iron-transferrin and phosphorylation of the transferrin receptor. Hemin gM) reduced iron transport but increased cell-associated transferrin. When intracellular iron delivery was inhibited by NH4Cl, no such increase in cell-associated transferrin was seen.During uptake of 125I-labeled transferrin in the steady state, the use of a washing technique to dissociate bound transferrin on the cell membrane showed that radioligand accumulated on the surface of hemin-treated cells. Hemin reduced the initial influx of transferrin, thereby diminishing incorporation of iron. Receptor phosphorylation was investigated by immunoprecipitation of reticulocyte extracts after metabolic labeling with[32p]p1. In the absence of ligand, phosphorylated receptor was chiefly localized on cell stroma. Exposure to transferrin increased cytosolic phosphorylated receptor from 15-30% to approximately 50% of the total, an effect overcome by hemin. treatment, Addition of hemin in the presence of transferrin enhanced net phosphorylated receptor in the reticulocyte in association with a redistribution of phosphorylated receptor to stromal membranes. The findings suggest a possible relationship of phosphorylation to endocytosis of the transferrin receptor in reticulocytes.

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Section: Gm) Reduced Iron Transport But Increased Cell-associated Tramentioning

confidence: 99%

Hemin inhibits internalization of transferrin by reticulocytes and promotes phosphorylation of the membrane transferrin receptor.

Cox¹,

O'Donnell²,

Aisen³

et al. 1985

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

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“…To our knowledge, this is the first report to demonstrate dissociation of heme moiety from the Hb molecule caused by an active metabolite of TNT. Early studies on heme biosynthesis in erythroid tissue have indicated that hemin itself inhibits the production of delta-aminolevulinic acid, a precursor for heme, both in vivo and in vitro (Karibian and London, 1965;Gallo, 1967). On the other hand, hemin induces heme oxygenase, the rate-limiting enzyme for heme degradation (Tenhunen et al, 1970).…”

Section: Fig 2 Effects Of Tnt and Its Metabolites On Hematotoxic Acmentioning

confidence: 99%

Participation of metabolic activation of 2,4,6-trinitrotoluene to 4-hydroxylamino-2,6-dinitrotoluene in hematotoxicity

Shinkai

Kikuchi

et al. 2015

J. Toxicol. Sci.

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-Exposure to 2,4,6-trinitrotoluene (TNT) causes methemoglobin (metHb) formation, hemolysis and negative heme balance in vivo, but the mechanistic details are poorly understood. In the present study, we examined the participation of metabolic activation in TNT-mediated hematotoxicity. Exposure of rats with TNT (300 mg/kg, i.p.) for 4 days resulted in a decrease of hematocrit value coupled to an increase in metHb formation. The red blood cells treated with 4-hydroxylamino-2,6-dinitrotoluene (HADNT), a metabolite of TNT, underwent readily hemolysis in vitro, whereas such a phenomenon was not seen with TNT. Consistent with this, HADNT is active toward metHb formation and the decrease in thiol content of the globin moiety compared with TNT and its metabolites 4-amino-2,6-dinitrotoluene (ADNT) and 4-acetylamino-2,6-dinitrotoluene (AADNT). Furthermore, interaction of purified rat oxyhemoglobin (oxyHb) with HADNT, but not TNT, ADNT, and AADNT, caused a concentration-dependent production of H 2 O 2 and ferrylhemoglobin (ferrylHb) which is a highly oxidizing state formed by reaction of oxyHb with H 2 O 2 . Notably, hemin was released during interaction of oxyHb with HADNT. Taken together, these findings suggest that HADNT is an active metabolite that mediates TNT-induced hematotoxicity via formation of prooxidants such as H 2 O 2 and ferrylHb.

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“…An inhibitory effect on erythropoiesis has with previous studies (Karibian & London been demonstrated in erythropoietin (ESF) 1965, Gallo 1967, Kilbridge et a1 1969 polycythaemic mice after injec -Ponka & Neuwirt 1969). However, some tions of intact red blood cells (RBC) or an authors have found a stimulatory effect on equal amount of haemolyzed cells (Linde-erythropoiesis with haemolysates, haeme mann 1974b).…”

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confidence: 89%

Erythropoiesis Inhibiting Factor(s) in Intact and Haemolyzed Red Blood Cells

Lindemann¹

1975

Scandinavian Journal of Haematology

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A previous report have shown that both intact red blood cells (RBC) and an equal number of haemolyzed cells were able to inhibit erythropoiesis on ESF-induced erythropoiesis, suggesting a cell compound to be responsible for the inhibitory effect. Haeme and haeme compounds have been found to stimulate or inhibit both erythropoiesis and haeme synthesis. The present work presents data on the inhibitory effect of haemolyzed RBC and compounds from intact RBC on erythropoiesis. The inhibiting factor was found to be of a small molecular size and of the same range as a urinary erythropoiesis inhibiting factor (EIF). The inhibitor did not contain haeme.Both Fez+ and Fe3+ were tested, showing no reduction of the 59Fe incorporation into RBC in the test animals. The inhibition could not be due to dilution of the 59Fe with unlabelled iron from the haemolyzed cells. On the contrary, Fe3+-ions rather stimulated erythropoiesis, probably due to increased amounts of available iron. Haemolysates were prepared from RBC with different amounts of immature cells. With increasing amounts of reticulocytes, a reduction of the inhibitory effect occurred. Also foetal cells showed less inhibition than an equal amount of adult cells. After high speed centrifugation, the inhibitory effect of haemolysates was found in the supernatant, while ghost cells exerted no inhibition. No species differences were found using both exhypoxic polycythaemic mice and rats. An inhibiting factor was liberated into the incubation medium when RBC were incubated for 20 h. No haemolysis occurred during the incubation period. Mature, adult RBC therefore contain a substance which is different from haeme, with a negative feedback on erythropoiesis.K e y words: erythropoiesis inhibiting factorerythrocyteshaemolysate

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The Inhibitory Effect of Heme on Heme Formation In Vivo: Possible Mechanism for the Regulation of Hemoglobin Synthesis*

Cited by 9 publications

References 20 publications

Hemin inhibits internalization of transferrin by reticulocytes and promotes phosphorylation of the membrane transferrin receptor.

Hemin inhibits internalization of transferrin by reticulocytes and promotes phosphorylation of the membrane transferrin receptor.

Participation of metabolic activation of 2,4,6-trinitrotoluene to 4-hydroxylamino-2,6-dinitrotoluene in hematotoxicity

Erythropoiesis Inhibiting Factor(s) in Intact and Haemolyzed Red Blood Cells

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