568 THE BIOCHEMISTRY OF B VITAMINS 



which has been attributed to decreased synthesis by intestinal bacteria, 

 affords a deficiency with which the efficacy of folic acid and its derivatives 

 can be evaluated for the rat. The effectiveness of folic acid in treatment 

 of pernicious anemia, 70-72 sprue, 73 and nutritional macrocytic anemia 70-72 

 has made available a means of demonstrating in human subjects the 

 activities of compounds related to folic acid. Increased excretion in the 

 urine of microbiologically active forms of folic acid on administration of 

 microbiologically inactive forms of the vitamin has also been used as a 

 criterion for the utilization of the compounds in human subjects. Although 

 only small amounts, less than 1 per cent of the normal total intake of 

 folic acid in human subjects, are regularly excreted in the urine in micro- 

 biologically active forms, 74,75 the administration of relatively large 

 amounts of folic acid (1-15 mg) often results in urinary excretion of 15 

 to 75 per cent of the administered dose within 24 hours ; 42, 76 however, 

 the amount excreted depends somewhat on the individual. 



Of the two optically active stereoisomers with the structure of folic 

 acid, only the naturally occurring L-modification appears to be biologi- 

 cally active, since the racemic modification is approximately half as effec- 

 tive as the naturally occurring folic acid for Lactobacillus casei and 

 Streptococcus faecalis R. 22 Also, D-folic acid (N-pteroyl-D-glutamic 

 acid) does not replace L-folic acid in stimulating the production of the 

 Rous sarcoma (p. 595) in folic acid-deficient chicks. 77 



Although N-pteroyl-a-glutamylglutamic acid is only about 1 per cent 

 as effective as folic acid in the nutrition of Lactobacillus casei and Strep- 

 tococcus faecalis R, 26, 36 this folic acid derivative is completely effective 

 for the chick, 36 and also replaces folic acid in stimulation of the Rous 

 sarcoma virus in folic acid-deficient chicks. 77 Administration of N-pteroyl- 

 a-glutamylglutamic acid (6.5 mg) either orally or intravenously to normal 

 male human subjects results in an increased excretion of folic acid 

 amounting to 50 to 75 per cent of that excreted when an equivalent 

 amount of folic acid (5 mg) is administered. 38 Although there is a lag 

 in the initial rate of excretion, particularly following intravenous admin- 

 istration, a major portion of the excretion takes place within the first 

 six hours. 38 Pteroyl-a-glutamylglutamic acid has also been reported to 

 be effective in treatment of pernicious anemia and macrocytic nutritional 

 anemia, but does not appear to be as active as folic acid. 39, 40 



Contrasting markedly to the corresponding a-glutamyl derivative, 

 N-pteroyl-y-glutamylglutamic acid is almost as active as folic acid for 

 Lactobacillus casei and Streptococcus faecalis R. 26 



With the exception of Streptococcus faecalis R, N-pteroyldi-y-glutamyl- 

 glutamic acid is essentially as effective as folic acid for all the organisms 

 listed in Table 18. With Lactobacillus casei and particularly with Strepto- 



