212 PTEROYLGLUTAMIC ACID 



tissue or that it is capable of producing nervous system damage in persons 

 other than patients with pernicious anemia or with related vitamin B12 

 deficiency states. The explanation of the effect of PGA in these situations 

 may lie in the aggravation of the B12 deficiency through exhaustion of the 

 small amount of available material. This theory is based in part on the 

 supposition that vitamin B12 functions in a number of metabolic pathways 

 which involve nervous as well as hemopoietic tissue, and it gains credence 

 from observations on the relationship of vitamin B12 to PGA metabolism. 

 These are discussed in the chapter on vitamin B12 . 



There remains to be considered the manner in which PGA deficiency 

 may develop in pernicious anemia and other conditions associated with a 

 lack of vitamin B12 . In the first place, it should be emphasized that the 

 deficiency of PGA may be more apparent than real, since much of the 

 difficulty may lie in the inability to utilize effectively PGA and its deriva- 

 tives which are present in the tissues in "bound" or conjugated forms. It 

 is known that PGA or related compounds, such as conjugates of PGA or 

 CF are present in the tissues of patients with pernicious anemia in relapse. ^^^ 



The impaired utilization of PGA in pernicious anemia may be due to 

 the presence of inhibiting substances, and one of the functions of vitamin 

 B12 may be to eliminate such inhibitors or overcome their influence. -°^ The 

 presence of a substance which inhibits the breakdown of pteroylheptaglu- 

 tamic acid to free PGA has been demonstrated in certain yeast concentrates, 

 fiver, and spinach.^^^' 2°^ In accordance with this theory, the therapeutic 

 efficacy of PGA may be due to a mass action effect overcoming the influence 

 of inhibitors. 



On the other hand, some degree of actual PGA deficiency is almost cer- 

 tainly present in patients with untreated pernicious anemia. The amount 

 of PGA contained in average diets is small, probably less than 1 mg. daily, 

 and most of it is in conjugated form. Reference has already been made to 

 the impaired utilization of pteroylheptaglutamic acid by pernicious anemia 

 patients. It has been shown that such persons on standard diets excrete 

 less PGA in the urine than is the case with normal subjects, and that, in 

 contrast to normal subjects, the administration of yeast concentrates con- 

 taining pteroylheptaglutamic acid is followed by little or no increase in 

 excretion of PGA.^^^' -°^ Following a short period of therapy with concen- 

 trated parenteral liver extract, pernicious anemia patients excrete free PG.V 

 after oral administration of its hexaglutamyl conjugate in amounts com- 



2«s R. W. Heinle, E. M. Nelson, and A. 1). Welch, Proc. Central Sac. Clin. Research 19. 



27 (1946). 

 2»6 M. ?:. Svvendseid, (). 1). Bird, H. A. Brown, and F. II. Bethell, J. Lab. Clin. Mc<t. 



32, 23 (1947). 

 2" A. D. Welch, R. W. Heinle, E. M. Nelson, and II. V. Nelson, J. Biol. Cheni. 164, 



787 (1946). 



