158 PTEROYLGLUTAMIC ACID 



which is characteristic of systems in which the antagonist blocks the enzyme 

 system at more than one point. The growth of chicks is retarded by 5 mg. 

 of 4-amino PGA per kilogram of diet. The toxicity is partially counteracted 

 by 5.0 mg. of PGA per kilogram of diet, but complete reversal is not at- 

 tained by as much as 25 mg. (Oleson et al}"^). In the rat, 10 7 of 4-amino 

 PGA per day or I mg. per kilogram of diet is lethal in about 3 to 4 days.*^ 

 The symptoms produced in the rat are severe diarrhea, weight loss, and 

 porphyrin-stained whiskers. Large amounts of PGA (20 mg. per kilogram 

 of diet) produced partial reversal of toxic symptoms. One milligram of 

 4-amino PGA per kilogram of diet produces high mortality in the mouse 

 which cannot be reversed by one hundred times as much PGA (Franklin 

 et al.Y^. Guinea pigs given 0.5 to 5.0 mg. of 4-amino PGA subcutaneously 

 daily lose weight and die within 11 to 28 days. The symptoms of toxicity 

 include normocytic anemia, leucopenia, agranulocytosis, thrombocytopenia, 

 and a hypoplastic bone marrow. PGA at levels of twenty-five to one 

 hundred times that of the analog prevents the development of leucopenia 

 but not the anemia (Minnich and Moore^^). 



Other animals which are susceptible to the action of 4-amino PGA are 

 the dog,^" the monkey,^^ and Drosophila.^^ Early embryonic death has been 

 induced in the dog and the mouse and rat.^^ The level of 4-amino PGA (0.1 

 mg. per kilogram of body weight) which was used to induce fetal death 

 produced a temporary depletion of the bone marrow and a transient loss 

 in body weight but did not make the animals seriously ill. 



The chick egg embryo is inhibited by 3 to 5 7 of 4-amino PGA.^^ The 

 inhibitor becomes relatively less toxic as embryonic development pro- 

 gresses.^^ Although PGA is almost completely ineffective in reversing the 

 action of the antagonist,^*' ^* a mixture of thymidine and hypoxanthine 

 desoxyriboside produced^* a partial reversal. Thymine plus hypoxanthine 

 desoxyriboside was ineffective. This provides a parallel to the action of 

 thymidine in reversing the action of 4-amino PGA in E. coli. and Le. 

 citrovorum and is the only example outside of microorganisms where thy- 

 midine is capable of reversing the action of a PGA antagonist. The citro- 



"J. J. Oleson, B. L. Hutchings, and Y. SubbaRow, J. Biol. Chem. 175, 359 (1948). 

 «« A. L. Franklin, E. L. R. Stokstad, and T. H. Jukes, Proc. Soc. Exptl. Biol. Med. 



67, 398 (1948). 

 89 V. Minnich and C. V. Moore, Federation Proc. 7, 276 (1948). 

 «« J. B. Thiersch and F. S. Philips, Proc. Soc. Exptl. Biol. Med. 71, 484 (1949). 



91 E. D. Goldsmith, M. H. Harnly, and E. B. Tobias, Ann. N. Y. Acad. Sci. 52, 1342 

 (1950). 



92 J. R. Thiersch and F. S. Philips, Proc. Soc. Exptl. Biol. Med. 74, 204 (1950). 



93 D. A. Karnofsky, P. A. Patterson, and L. P. Ridgvvay, Proc. Soc. Exptl. Biol. Med. 

 71, 447 (1949). 



9^ E. E. Snoll and W. W. Cravens, Proc. Soc. Exptl. Biol. Med. 74, S7 (1950). 



