VITAMINS, ANTIBIOTICS, AND GROWTH 349 



of intestinal bacteria but rather to a change in their type. The exact 

 nature of the change is not known, and the complexity and variability 

 of the normal intestinal flora make it difficult to determine. 



Certain antibiotics, such as penicillin and the tetracyclines, have 

 been shown to alleviate partial deficiencies of B-complex vitamins 

 when added to the diets of experimental animals, especially rats. Ap- 

 parently the change in the intestinal flora produced by the antibiotic 

 results in an increased production of thiamine and other vitamins, so 

 that the deficiency is alleviated. In the case of rats, the increased 

 supply is obtained mainly through coprophagy. 



Effects of vitamin antagonists 



Chemists have prepared a large number of synthetic compounds 

 which are anti-metabolites, or antagonists of the vitamins. These com- 

 pounds interfere with the coenzymatic functions of the vitamins by dis- 

 placing the normal coenzyme from its combination with the apoen- 

 zyme. The folic-acid antagonists are some of the most active com- 

 pounds in the vitamin-antagonist group. Nelson and co-workers (1957) 

 have studied in considerable detail the efiFects of folic-acid antagonists 

 on embr>'0 development in the rat and have described the deformities 

 produced in rat fetuses. One of the most potent of all vitamin antago- 

 nists is aminopterin, 4-aminopteroyl-glutamic acid, which in small doses 

 produces widespread pathological changes in animals, including sto- 

 matitis, dermatitis, alopecia, pharyngitis, ulceration of the gastro-intes- 

 tinal tract and of the buccal, vaginal, and rectal mucosa. The effects of 

 aminopterin are reversed by tetrahydrofolic acid or its 5- and 10-formyl 

 derivatives and the related ring compounds, 5,10-methenyl and 5,10- 

 methylene tetrahydrofolic acid, but they are not reversed to any appre- 

 ciable extent by folic acid itself. Aminopterin is a powerful and irre- 

 versible inhibitor of dihydrofolic reductase, the enzyme that hydrogen- 

 ates folic acid and dihydrofoHc acid. The behavior of aminopterin may 

 be explained by its action in "trapping" dihydrofolic acid, formed in 

 the thymidylate synthetase reaction from deoxyuridyHc acid and 5,10- 

 methylenetetrahydrofolic acid, and thus preventing the regeneration 

 of tetrahydrofolic acid from dihydrofolic acid. This is shown in 

 Figure 11. The abbreviations are FAH4 = tetrahydrofolic acid; 5- (or 

 10-)CHOFAH4 = 5- (or 10-)formyltetrahydrofoHc acid; 5, 10- 

 CHFAH4+ = 5, 10-methenyltetrahydrofolic acid; FAHo = dihydro- 

 foHc acid; FA = folic acid; 5-CHNHFAH4 = 5-formiminotetrahydro- 

 folic acid; 5, IO-CH2FAH4 = 5, 10-methylenetetrahydrofolic acid; FIG 

 = formiminoglycine; FIGlu = formiminoglutamic acid; FClu = 

 formylglutamic acid; GAR = glycinamide ribotide; FGAR = formyl- 



