The effect of cobalt on heme synthesis by bone marrow in vitro.

Since the demonstration by Waltner and Waltner (1) that cobalt will produce a polycythemia in rats, this effect has been produced in various other laboratory animals and human beings. However, the mechanism by which cobalt produces erythroid hyperplasia of the bone marrow remains obscure. This unique action of cobalt continues to be of interest because of its importance in leading to a better understanding of erythropoiesis and because of the possible therapeutic rBle of cobalt in various anemias. There have been a number of attempts to explain cobalt polycythemia in terms of an anoxic mechanism (2). Barron and Barron (3) observed an inhibition of the respiration of immature red cells by small amounts of cobalt. They concluded that this inhibition led to premature release of young red cells into the circulation and hence to polycythemia. However, Warren et al. (4) were not able to confirm these findings. They observed that cobalt in concentrations of 1.0-4 to 1O-2 M did not interfere w&h the respiration of bone marrow or reticulocytes in vitro unless. the concentration was as high as 0.01 M. Attempts have been made to link cobalt with the cytochrome system of biological oxidat.ion. Schultze (5) noted a close relat,ionship between the cytochrome oxidase activity of the bone marrow and the ability to form hemoglobin. Levey (6) gave intravenous injections of cytochrome c to cobalt-polycythemic rats, but failed to abolish the polycythemia. However, it was pointed out that cytochrome c administered intravenously does not appear in tissue cells. Although the hypothesis that cobalt produces cellular anoxia is an attractive one, the experimental evidence does not justify such an assumption. Attempts to explain cobalt polycythemia in terms of cellular bone marrow anoxia are made difficult by the fact that anoxia itself has not been shown to stimulate bone marrow directly (7). The development of a method for measuring hemoglobin synthesis by bone marrow in vitro by measuring the rate of incorporation of radio-