496 VITAMIN Bi2 



pothesis that intrinsic factor may function within the tissues are the obser- 

 vations of Lajtha,^^ confirmed by Thompson^^ and by Franco and Arkun,^* 

 that free B12 added to marrow culture medium, unlike PGA, will not cause 

 transformation, or "ripening," of megaloblasts into normoblasts. Callender 

 and Lajtha^^ have subsequently shown that, whereas gastric juice when 

 added by itself to such a marrow preparation has no ripening effect on 

 megaloblasts, the combination of B12 and gastric juice will cause such ele- 

 ments to ripen into normoblasts. They interpret this observation as in- 

 dicating that the hemopoietic activity of B12 is dependent upon the presence 

 of the vitamin in a complex containing an ''intrinsic factor," Gastric juice 

 contains such a factor, and Ross has shown that, after parenteral adminis- 

 tration to pernicious anemia patients, B12 is bound in a form which is 

 unavailable to test organisms. ^^ Since pernicious anemia serum, even with 

 added free B12, will not permit ripening of megaloblasts in vitro, the ques- 

 tion arises as to why the free vitamin should be so highly efficacious when 

 administered intravenously, or by other parenteral routes, to patients with 

 pernicious anemia. Callender and Lajtha^* attempt to explain this fact by 

 suggesting that an extragastric intrinsic factor, not present in the free form 

 in plasma, exists in the tissues of patients with pernicious anemia. They 

 are in accord with the view that PGA (folic acid) or one of its derivatives 

 acts directly on marrow cells but that, in pernicious anemia, such action is 

 prevented by an inhibitor. The function of the inhibitor is counteracted by 

 B12 when the latter is bound to gastric intrinsic factor in the case of marrow 

 culture, or to a tissue factor when the vitamin is introduced in vivo. Evi- 

 dence for the existence of such an inhibitor was afforded by earlier 

 studies^^' ^^ in Avhich Lajtha and his associates showed that the serum of 

 untreated pernicious anemia patients, in suitable concentrations, would not 

 induce ripening of megaloblasts in tissue culture, but that after dilution, 

 without the addition of any other factor, ripening of megaloblasts to nor- 

 moblasts occurred. These findings have been confirmed by Thompson work- 

 ing in Ungley's laboratory.^- 



Whether through counteraction of an inhibitor or some other mechanism, 

 the studies discussed above should provide at least a partial explanation 

 for the observation of Horrigan et at}'' that B12 instilled into the bone mar- 

 row of pernicicus anemia patients causes transformation of megaloblastosis 

 to normal erythropoiesis, whereas the instillation of PGA, and probably 



" L. G. Lajtha, Clin. Sci. 9, 287 (1950). 



32 R. B. Thompson, Clin. Sci. 9, 281 (1950). 



33 J. Franco and S. N. Arkun, Istanbul Contrib. Clin. Sci. 1, 92 (1951). 



34 S. T. Callender and L. G. Lajtha, Blood 6, 1234 (1951). 



35 G. I. M. Ross, Nature 166, 270 (1950). 



3« I. Ruszny^k, S. Lowinger, and L. G. Lajtha, Nature 160, 757 (1947). 

 37 D. Horrigan, T. Jarrold, and R. W. Vilter, /. Clin. Invest. 30, 31 (1951). 



