Abstract. The per cent Fe59 incorporation into circulating erythrocytes as an indicator for new hemoglobin production was used in the polycythemic exhypoxic mouse system to study the effects of certain steroid hormone metabolites on erythropoiesis. Enhanced Fe59 incorporation was observed after the administration of several metabolites with a 5,3-H configuration, while those with a 5a-H configuration had no stimulatory effect. The stimulatory effect in avian systems has been shown by others to be due to an increased activity of 6-aminolevulinic acid synthetase, the limiting enzyme in heme biosynthesis. These in vivo studies thus indicate that in this mouse system, as in previously reported studies with avian and human bone marrow cells, some steroid metabolites stimulate hemoglobin synthesis. The observation that the same structure-junction relationship exists in the currently described system as in the avian suggests that these steroids probably induce 6-aminolevulinic acid synthetase in the mouse. The erythropoietic action of these nonandrogenic steroid metabolites may prove to be clinically useful.Recent studies by Granick and Kappas'-1 and Levere et al.4 have indicated a possible role for steroid metabolites with a 5fl-H configuration, in regulating porphyrin-heme biosynthesis via their ability to induce the de novo formation of 6-aminolevulinic acid synthetase, the rate-limiting enzyme in this pathway. The tissues in which 5-aminolevulinic acid synthetase was shown to be inducible by these steroids included the avian embryo liver and the erythroid cell precursors of the chick blastoderm. Unlike certain porphyria-inducing drugs, such as allylisopropylacetamide, which could induce 5-aminolevulinic acid synthetase in liver cell cultures but failed to do so in the chick blastoderm, the steroid metabolites were active in both tissues. A working hypothesis was presented which suggested that these metabolites may act as derepressor agents for the structural gene coding for 5-aminolevulinic acid synthetase, permitting it to transcribe more actively, leading to enhanced formation of this enzyme and thus to increased production of heme. If this formulation were correct, one could predict that these steroid metabolites might be able to regulate heme synthesis in other types of cells where 5-aminolevulinic acid synthetase was inducible such as the hepatic or erythroid tissues of other species.It was the purpose of this study to test this question by examining the effects 564
In mice 5beta(H) steroids have been shown tostimulate heme synthesis in vivo. The current studies were undertaken to evaluate the effect of these steroids on heme synthesis by use of the "well" method of marrow culture. The 5beta(H) steroid metabolites 3alpha-hydroxy-5beta-pregnane-11, 20-dione, 3beta-hydroxy-5beta-pregnan-20-one, 3 alpha,17alpha-dihydroxy-5beta-androstan-3-one stimulated Fe uptake by human marrow explants cultured in wells. The dibutyrl analog of adenosine 3',5'-monophosphate (db cAMP) also stimulated Fe uptake. The effect of the latter compound was enhanced by theophylline. There was no additive nor synergistic effect between db cAMP and the 5beta(H) steroid metabolites. There was no inhibition of the steroid metabolite effect by either antierythropoietin serum or cyproterone. Uptake of fe was also enhanced by the cations Ca++ and Co++.
The comparative erythropoietic activity of eight androgens in mice is reported. Polycythemic mice were used in the posthypoxic interval for determination of 59Fe utilization and reticulocyte count. The most potent compounds were 19-nortestosterone decanoate and 19-nortestosterone phenylpropionate. The mechanism of erythropoietic stimulation by 19-nortestosterone decanoate is similar to that of testosterone.
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