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The effect of cobalt ions on the biosynthesis of hemoglobin by rabbit reticulocytes in vitro has been studied. It is shown that cobalt ions in concentrations of approximately 10‐3 M almost completely inhibit the formation of heme, while the formation of globin is unaffected or slightly stimulated. The inhibiting effect on heme formation is found to be due to inhibition of the formation of the tetrapyrrolic intermediates in heme formation, while the conversion of the 8 carboxylic intermediate by stepwise decarboxylation and finally dehydrogenation and iron incorporation is unaffected. The implications of the above findings for the understanding of the effect of cobalt ions on the erythropoiesis are discussed, and it is suggested that the polycythemia induced by cobalt ions may be due to a toxic effect of the metal on hemoglobin formation with a secondary stimulation of red cell formation. The possibility that cobalt may exert a directly stimulating effect on the formation of erythropoietine is not, however, excluded.

It has been shown that tetrapyrroles having from 4 to 8 carboxylic groups of both the III and I isomer series are formed by rabbit reticulocytes in vitro under hypoxic conditions. The tetrapyrroles of the III series are rapidly converted into protoporphyrin under aerobic conditions, while the tetrapyrroles of the I series are converted into coproporphyrinogen I. The implications of these findings have been discussed and it is suggested that an 8‐carboxylated openchained tetrapyrrolic intermediate of the I series is normally formed by a deaminase, the so‐called porphobilinogenase, and that this tetrapyrrole is condensed spontaneously into uroporphyrinogen I if this condensation is not hindered by a second enzyme, the so‐called isomerase. The possible effect of the latter is discussed and a scheme for the formation of ringformed tetrapyrroles of both the III and I series has been suggested. It is further suggested that the formation of ringformed tetrapyrroles of the I series is due to inhibition or blockage of the isomerase with spontaneous condensation into uroporphyrinogen I of the openchained tetrapyrrole of the I series formed by the deaminase, uroporphyrinogen I being rapidly converted by the decarboxylases present into coproporphyrinogen I. The accumulation of the latter when the atmosphere is changed into air, shows that the enzymes responsible for the conversion of coproporphyrinogen into protoporphyrin are highly specific and can utilize only coproporphyrinogen III and explains why porphyrins having less than 4 carboxylic groups have been found in nature only as isomers of the III series.

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