THE FOLIC ACID GROUP 571 



this conjugate and the triglutamate, on a molar basis, are as active as folic 

 acid for Tetrahymena gelii W. 62 Earlier work on a deficient medium indi- 

 cated the possibility that these conjugates may be more effective than 

 folic acid. 63 



Oral or parenteral administration of pteroylhexaglutamylglutamic acid 

 to normal human subjects produces a prompt excretion of microbiolog- 

 ically active forms of folic acid. On daily administration of equivalent 

 amounts of the conjugate or folic acid (4 mg), comparable amounts of 

 microbiologically active forms of folic acid (approximately 30-35 per cent 

 of the administered dose) are excreted daily. 46 A normal subject given 

 2.8 mg of the conjugate daily by intramuscular injection excreted 8.3 

 per cent of microbiologically active forms equivalent to folic acid, whereas 

 administration of an equivalent amount of folic acid resulted in the 

 urinary excretion of 16 per cent of microbiologically active forms. 47 Oral 

 administration of pteroylhexaglutamylglutamic acid (equivalent to 8.4 

 mg of folic acid daily) caused a rapid clinical improvement in a patient 

 with sprue; however, only small amounts of microbiologically active 

 forms of the vitamin were excreted in the urine. 42 The conjugate appears 

 to be similarly active in nutritional macrocytic anemia. 39,51 



However, the ability of pernicious anemia patients to utilize the conju- 

 gate appears to vary. 48 Many patients in relapse respond hematologically 

 and excrete increased amounts of folic acid following the administration 

 of pteroylhexaglutamylglutamic acid. 39, 49_51 Yet there are reports of 

 failure by pernicious anemia patients in relapse to respond either hema- 

 tologically or with increased excretion of microbiologically active forms 

 of the vitamin. 47 - 50, 52 Quantities as high as 54 mg of the conjugate admin- 

 istered daily in exceptional cases of pernicious anemia have failed to 

 increase the urinary excretion of microbiologically active forms of folic 

 acid. 50 It has been demonstrated that even in normal individuals the 

 ability of the conjugate to cause increased urinary excretion of micro- 

 biologically active forms of folic acid can be almost completely inhibited 

 by administration of a conjugate preparation containing conjugase in- 

 hibitor or by administration of yeast extract 46 which contains consider- 

 able amounts of conjugase inhibitor. 88 No evidence for the excretion of the 

 conjugate as such has been found. 46 



Nucleic acid, 89 proteins, 90 and a p-aminobenzoylpolyglutamyl derivative 

 of an unidentified amino acid, 91 which has been isolated from yeast, 92 

 inhibit the conjugase enzyme. The inhibition with the polypeptide is com- 

 petitive. 91 Conjugase inhibitors appear to be widely distributed in nature 

 and are known to occur in liver and spinach as well as in yeast. 46 It has 

 been suggested that the conjugase inhibitors may play an important role 

 in the utilization of the conjugate and may account for at least some of 



