The responsiveness to erythropoietin of cultured bone marrow cells, obtained from 7 patients with refractory anemia with hyperplastic marrow, was studied. 5 of these patients' marrows also exhibited sideroblastic changes. Heme synthesis in cultured bone marrow cells was either responsive to stimulation by erythropoietin, or completely refractory. The sensitivity of the bone marrow cells to the hormone was not related to either the clinical or laboratory findings
A new technique for the intracellular localization of minute amounts of heme and hemoproteins is described. The specimen is treated with 1.5 M perchloric acid in the presence of SH groups, followed by ultraviolet light irradiation in a fluorescence microscope. This fixes the proteins in situ and converts the heme to a porphyrin which fluoresces and is readily visualized. With this technique, hemoglobin has been demonstrated in the nuclei of avian erythrocytes, and in the nuclei of human normoblasts at an earlier stage than previously described. In addition, hemoproteins, presumably cytochromes, have been detected in the cytoplasm and nuclei of myelocytes, in thymus lymphocyte nuclei, in chick embryo liver cytoplasm, and in chick embryo somites.
HYPERCHOLESTEROLEMIA occurs in some patients with inherited hepatic porphyrias1 , 2 and also in laboratory animals with chemically induced hepatic porphyria.2 To define the nature of the disturbance in lipoprotein metabolism implied by this hypercholesterolemia,3 , 4 we have measured the concentrations of the various lipoproteins in the plasma of patients with the well defined hereditary hepatic porphyria, acute intermittent porphyria (AIP). The initial results of this study are reported here.Methods and ResultsEach of the 10 patients studied had AIP well documented by personal and family history and by several chemical criteria (Table 1).5 Blood was drawn, and the lipoproteins quantitated as . . .
Abstract Renal failure, which developed in two patients with sickle-cell anemia, was treated by maintenance hemodialysis for six and seven months. Medullary cystic disease appeared to cause the uremia in a 32-year-old black man with sickle-cell anemia; in the second patient, a 24-year-old black woman, histologic changes in a renal biopsy were consistent with So-Called sickle nephropathy. When uremia supervened each patient's transfusion requirement, which had been stable at 2 units per month, increased abruptly to 5 and 6 units per month, and then fell, upon initiation of maintenance hemodialysis, to 1 unit per month. Vascular access for dialysis was provided by an internal arteriovenous fistula in one patient and an arterioarterial bovine carotid heterograft in the other. There were neither hemorrhagic nor thrombotic complications of the dialysis regimen. Coincident congestive heart failure in both patients responded well to digitalis. (N Engl J Med 291: 431–435, 1974)
Heme oxygenase, the rate-limiting enzyme in the degradation of heme to bile-pigments and carbon monoxide, is induced in response to increased oxidative stress and is believed to provide a cytoprotective effect. We investigated the role of heme oxygenase in cultured rabbit corneal epithelial cells (RCE), and its potential to alleviate oxidative stress-induced cell damage. Heme oxygenase in RCE was effectively and potently induced by most metals tested, including tin, silver, and gold, and cytokines such as IL-6, and TGFβ. Stannous chloride and heme-induced heme oxygenase mRNA by 40 and 100 fold within 1-3 hours and increased enzyme activity by 9.2- and 10-fold, respectively, over a 24 hour period. IL-6, TGFβ and H2O2 induced heme oxygenase by 2-3 fold. Zinc protoporphyrins were effective inhibitors of heme oxygenase activity in vitro. However, when incubated with cells for 24 h they induced heme oxygenase mRNA but decreased or had no effect on its activity.
Heme oxygenase, the rate-limiting enzyme for heme degradation, can be inhibited by several new synthetic metalloporphyrins. Under certain conditions, a depression in heme oxygenase activity has important clinical significance in the treatment of hyperbilirubinemia, and, in this regard, tin-protoporphyrin has been shown to decrease the production of bilirubin in vitro as well as in vivo. Similarly, our study was concerned with finding a new metalloporphyrin which will inhibit heme oxygenase. Many of the synthetic heme analogs that we analyzed were quite effective inhibitors of heme oxygenase, but the most powerful inhibitor was found to be zinc-deuteroporphyrin IX, 2,4-bisglycol. This metalloporphyrin almost completely inhibits liver heme oxygenase at concentrations as low as 0.5 microM. Its potency as an inhibitor was found to be greater than that of tin-protoporphyrin; the Ki of zinc-deuteroporphyrin IX, 2,4-bisglycol was calculated to be 0.003 microM. In conclusion, we demonstrated that zinc-deuteroporphyrin IX, 2,4-bisglycol has potent inhibitory effects on human liver, kidney and brain heme oxygenase so that this metalloporphyrin can be considered as an alternative to tin-protoporphyrin in the treatment of hyperbilirubinemia.
