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Thyminnucleotid-Synthese und Proliferation von Knochenmarkzellen bei megaloblastären Anämien unter der Einwirkung von Vitamin B12

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Zusammenfassung

Am Knochenmark von vier Patienten mit megaloblastären Anämien wurden vor und nach i.m. Injektion von 1000 µg Vitamin B12 in Form von Cyanocobalamin die bei der Thyminnucleotid-Synthese beteiligten Enzyme FH2-Reductase und Thymidinkinase, der Mitoseindex, der DNS-Gehalt in der Einzelzelle und der in vitro-Einbau von3H-Thymidin untersucht:

  1. 1

    Der Anteil in DNS-Synthese befindlicher Zellen ist in der megaloblastären Erythropoese und Granulopoese im Durchschnitt erhöht. Dieses läßt sich innerhalb der Erythropoese auf einen hohen3H-Thymidinindex der polychromatischen Megaloblasten zurückführen. Bei der Untersuchung der Granulopoese fallen unter den „Riesenstabkernigen“ ein besonders hoher3H-Thymidin-Markierungsindex und gehäuft 4 n DNS-Werte auf. Diese Zellen werden als nicht ausreifungsfähige Fehlbildungen auf der Stufe der Pro- und Myelocyten aufgefaßt.

  2. 2

    Nach Vitamin B12-Gabe fallen3H-Thymidinindex und Anteil der Zellen mit einem DNS-Gehalt zwischen 2 n und 4 n mit Normalisierung des morphologischen Markbefundes auf niedrige Werte ab. Diese Veränderungen erfolgen in der Erythropoese schneller als in der Granulopoese.

  3. 3

    Im Cytolysat des megaloblastären Knochenmarkes ist besonders die Thymidinkinase stark erhöht. Ein beginnender Aktivitätsabfall dieses Enzyms kann bereits 12 Std nach Vitamin B12-Gabe nachgewiesen werden. Dieses läßt sich durch Normalisierung der de-novo-Synthese von Thyminmethylgruppen und Hemmung der Thymidinkinase durch vermehrt gebildetes Thymidintriphosphat erklären. Auch die erhöhte FH2-Reductase fällt nach Vitamin B12-Gabe auf normale Werte ab.

  4. 4

    Der Wirkungsmechanismus des Vitamin B12 und die bei seinem Mangel resultierenden Veränderungen im Zellstoffwechsel und in der Proliferation werden diskutiert. Dabei wird für die Megaloblasten eine verlängerte DNS-Synthesedauer angenommen.

Summary

The enzymes FH2-reductase and thymidine kinase which are important for thymine nucleotide-synthesis, the DNA-content of single cells and the in vitro incorporation of3H-thymidine were examined in the bone marrow of 4 patients with megaloblastic anemias before and after i.m. injection of 1000 µg vitamine B12 as cyanocobalamine.

  1. 1

    Prior to injection of vitamine B12 the number of DNA synthesizing cells is increased in the megaloblastic erythropoietic and in the granulopoietic system. Within the erythropoiesis this is due to a high3H-thymidine-index of polychromatic megaloblasts. Examination of the granulopoiesis shows high3H-thymidine indices and many 4n DNA-values of the giant band cells. These cells seem to be defect precursors — unable to mature — in the compartment of promyelocytes and myelocytes.

  2. 2

    After injection of vitamin B12 there is a decrease of3H-thymidine-index and of cells with DNA-content between 2 n and 4 n to normal values simultanously with morphological restauration of the bone marrow. These changes are detected in the erythropoiesis earlier than in the granulopoiesis.

  3. 3

    In the cytolysate of the megaloblastic bone marrow the thymidine kinase is highly increased. A decrease of this enzyme activity can be detected already 12 hours after injection of vitamine B12. This may be explained by normalisation of de novosynthesis of thymine methylgroups, for thymidine-triphosphate which is formed by this pathway has an inhibitory action on thymidine kinase. The activity of FH2-reductase also is increased and falls down to normal values after application of vitamine B12.

  4. 4

    The mechanism of action of vitamine B12 and the abnormalities of cell metabolism and proliferation in B12-deficiency are discussed. It seems probable that in the cells of the megaloblastic bone marrow the DNA-synthesis is prolongated.

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  1. Medizinische Universitätsklinik Tübingen, Germany

    H. E. Bock, J. Hartje, D. Müller & W. Wilmanns

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Bock, H.E., Hartje, J., Müller, D. et al. Thyminnucleotid-Synthese und Proliferation von Knochenmarkzellen bei megaloblastären Anämien unter der Einwirkung von Vitamin B12 . Klin Wochenschr 45, 176–188 (1967). https://doi.org/10.1007/BF01716905

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