Disease relevance of phenylhydrazine

• Hepcidin mRNA levels were assessed in two models of anemia, acute hemolysis provoked by phenylhydrazine and bleeding provoked by repeated phlebotomies [1].
• After cessation of treatment with PHZ, mid-stage RLV-A-infected, anemic mice responded with massive reticulocytoses and a rebound in hematocrit above control levels [2].
• Western blot analysis of cytoplasmic extracts from Rauscher murine erythroleukemia cells and phenylhydrazine-treated mouse splenic erythroid cells revealed the presence of several PDGF-like proteins [3].
• To address this question, we have isolated nucleated red cell precursors and reticulocytes from spleens and from the peripheral blood, respectively, of rats with phenylhydrazine-induced hemolytic anemia and pulse-labeled them with [35S]methionine [4].
• We found that treatment of normal RBCs with phenylhydrazine produced rigid and mechanically unstable membranes in conjunction with selective association of oxidized alpha-globin chains with the membrane skeleton, features characteristic of RBCs in severe beta-thalassemia [5].

High impact information on phenylhydrazine

• However, when cells were exposed to agents that oxidize cell proteins (nitrite or phenylhydrazine), the degradation of erythrocyte proteins to amino acids increased 7- to 33-fold [6].
• Increased erythropoietic activity induced by treatment of adult mice with phenylhydrazine ( PHZ ) resulted in a seven- to eightfold increase in the frequency of spleen and bone marrow cells expressing this gp70 [7].
• The treatment of infected polycythemic chimeras with phenylhydrazine lowered the hematocrit and restored the synthesis of B10.D2 hemoglobin [8].
• Using a serum-free biologic assay, PDGF-like biological activity was found in cell lysates and conditioned medium of both Rauscher cells and phenylhydrazine-treated mouse erythroid cells [3].
• Erythrocyte membrane lipid peroxidation was induced in rats by administering phenylhydrazine, an oxidant drug [9].

Chemical compound and disease context of phenylhydrazine

• We have evaluated transport of Na+ and K+ in erythrocytes of patients with thalassemias as well as in two experimental models that use normal human red blood cells, one for alpha thalassemia (methylhydrazine treatment, alpha thalassemia like) and one for beta thalassemia (phenylhydrazine treatment, beta thalassemia like) [10].
• This permits a quantitative comparison of the adenylate cyclase activity of reticulocyte membranes which had been induced either by bleeding (30% reticulocytosis) or by repeated injections of phenylhydrazine (90% reticulocytosis) [11].
• RESULTS: Phenylhydrazine hydrochloride injection resulted in a blunted response of normal tissues to Photofrin-mediated PDT-induced edema formation [12].
• Hemolytic anemia induced in mice by phenylhydrazine injection also did not affect duodenal ascorbate concentrations [13].
• Protective effect of the flavonoid silybin dihemisuccinate on the toxicity of phenylhydrazine on rat liver [14].

Biological context of phenylhydrazine

• The cardiac output and the percentage of blood flow to the marrow was increased in phenylhydrazine-treated and bled animals [15].
• Importantly, stimulation of normal erythropoiesis in vivo in mice treated either with phenylhydrazine or with erythropoietin increased PDGF levels in the spleen by 11- to 48-fold and 20- to 34-fold, respectively [16].
• Phagocytosis of phenylhydrazine oxidized and G-6-PD-deficient red blood cells: the role of cell-bound immunoglobulins [17].
• Neutralizing quantities of the ACK2 antibody reduced femoral CFU-E, BFU-E, and CFU-GM content to less than half that found in phenylhydrazine-treated control mice and nearly totally ablated splenic hematopoiesis [18].
• STAT1-deficient erythroblasts from phenylhydrazine-primed mice displayed enhanced phosphorylation of STAT5a/b, Erk1/2, and protein kinase B (PKB)/Akt [19].

Anatomical context of phenylhydrazine

• A very small but detectable amount of correctly initiated embryonic p-type globin RNA was detected in reticulocytes from birds treated with 5-azacytidine, while none was detected in reticulocytes from those receiving only phenylhydrazine or phenylhydrazine plus 1-beta-D-arabinofuranosylcytosine (cytosine arabinonucleoside) [20].
• No cell lines were obtained from uninfected adult, newborn, or phenylhydrazine-treated animals with or without CM [21].
• When injected HeLa cells were treated with phenylhydrazine to denature the cotransferred hemoglobin, a series of prominent ubiquitin-globin conjugates appeared [22].
• With 100 mg/dL phenylhydrazine, when the entire membrane was coated with Heinz bodies, RBC filterability and membrane deformability were drastically reduced [23].
• During phenylhydrazine-induced acute anemia, numbers of both the EP population and CFU-E colonies increase [24].

Associations of phenylhydrazine with other chemical compounds

• Both the effect of phenylhydrazine on erythrocyte membrane lipid peroxidation and alterations in phospholipid organization and coagulability were blocked when rats were simultaneously administered with vitamin E or C antioxidants [9].
• In this study, stress induced by 5-fluorouracil or phenylhydrazine revealed a delay in the recovery of erythroid progenitors, early precursors, and normal hematocrits in Cul4A(+/-) mice [25].
• Hepatic removal of RBC previously treated in vitro with N-ethyl-maleimide (NEM) or phenylhydrazine-HCl (PHZ) was similarly depressed by pretreatment with cortisone [26].
• In addition, the regeneration of erythroid and myeloid progenitor cells is delayed during stress hematopoiesis induced by phenylhydrazine or by 5-fluorouracil, suggesting impairment in early progenitor expansion in the absence of alpha4 integrin [27].
• Scaling the portal to central vein distance and taking 1 as the portal vein point and 0 as the central vein point, the relative position of hemopoietic foci, indirectly calculated from succinate dehydrogenase activity values, was 0.35 +/- 0.13 in postnatal livers and 0.73 +/- 0.12 in phenylhydrazine-treated adult livers [28].

Gene context of phenylhydrazine

• We studied the interaction of this labeled recombinant EPO with erythroid precursor cells from mice made anemic with phenylhydrazine [29].
• The levels of total and of distal, but not of proximal, Gata1 transcripts increased by five- to eightfold during in vivo and in vitro differentiation of FVA and PHZ cells [30].
• We detected high levels of SMARCA5 mRNA in murine bone marrow and spleen and monitored its expression in these hematopoietic tissues during accelerated hematopoiesis following hemolytic anemia induced by phenylhydrazine [31].
• Accelerated erythropoiesis following phenylhydrazine-induced hemolytic anemia, however, was comparable between Cox-2-/- and Cox+/- mice, as were induced levels of renal erythropoietin mRNA [32].
• The possibility that IL-3 and GM-CSF may act by modulating Epo receptor expression was investigated using erythroblasts purified from the spleens of phenylhydrazine-treated mice [33].

Analytical, diagnostic and therapeutic context of phenylhydrazine

• With phenylhydrazine concentrations below 30 mg/dL, even in the presence of multiple Heinz bodies, the RBC deformability measured by filtration through 2.6-, 4.5-, and 6.8-microns pores and the membrane deformability determined by a filter aspiration technique were not altered [23].
• This lack of an ATP requirement means that the degradation of oxidant-damaged proteins does not require ligation to ubiquitin (even though phenylhydrazine treatment does make hemoglobin a very good substrate for ubiquitin conjugation) [34].
• The oxidative metabolism of hydralazine, isoniazid, iproniazid, and phenylhydrazine has been studied using spin-trapping techniques [35].
• UV-vis spectroscopic pH titration of phenylhydrazine adducts of 1(ox) and 4, 2, and 11, respectively, reveals a similar red shift in lambda(max) at alkaline pH with the same pK(a) (approximately 11.8) [36].
• Splenectomy or injection of doses of phenylhydrazine-treated RBC which depressed splenic clearance function increased the susceptibility to septic peritonitis induced by cecal ligation and puncture [37].

References