578 THE BIOCHEMISTRY OF B VITAMINS 



in the appearance of symptoms characteristic of folic acid deficiency (p. 

 413). Thus, L-z-methylfolic acid inhibits competitively the utilization of 

 folic acid in rats fed a purified diet supplemented with succinylsulfa- 

 thiazole. 107 The analogue-folic acid ratio at which the deficiency symp- 

 toms appear is approximately 3000. The deficiency symptoms produced at 

 this ratio and more acutely at higher ratios of analogue to vitamin include 

 reduced rate of growth, lowered hemoglobin values, and pronounced re- 

 duction of the white cell count, with a greater reduction in granulocytes 

 than in lymphocytes. Inanition and severe diarrhea develop, the fur 

 becoming rough and unkempt in appearance. A red pigment accumulates 

 about the vibrissae, and necrotic and ulcerative changes are produced in 

 the oral cavity, particularly in animals which die. The oral lesions pro- 

 duced with the antagonist are usually not characteristic of a folic acid 

 deficiency in rats, but are produced by folic acid deficiency in the 

 monkey. 110 In such animals, a general necrotic condition within the 

 mouth and inflamed lungs with considerable congestion are noted. The 

 gastrointestinal tracts of most animals are empty and atonic; the livers, 

 spleens, hearts and other organs except the genital system are normal in 

 size and appearance, but uteri are always small and atrophic. In the 

 bone marrow, the maturation of cells of the erythroid series and of granu- 

 locytes are seriously impaired. If animals are treated with sufficient folic 

 acid just prior to the expected appearance of the terminal moribund 

 state, which usually occurs within one to two weeks after the onset of 

 the syndrome, the rats recover rapidly and appear normal within four 

 weeks. After recovery, the only abnormal effect is an enlarged spleen, 

 which in some cases is four times the normal size. 107 



Although female mice on a purified basal diet containing succinylsulfa- 

 thiazole do not develop deficiency symptoms within six weeks, supple- 

 mentation of the diet with crude L-z-methylfolic acid (10 g per kg) 

 results in death of a majority of the animals within six weeks, and the 

 surviving animals are left in a moribund condition. 111 These surviving 

 animals are emaciated but do not have the chromodacryorrhea, ruffled 

 fur, and other characteristics of rats similarly treated. The livers are 

 yellow, though normal in size and texture, but the uteri are atrophic. In 

 contrast to the rat, in which the reduction of the granulocyte count is 

 more pronounced, the cells of both the myeloid and lymphoid series are 

 inhibited to almost the same extent by methylfolic acid in the mouse. 

 Since complete protection against the analogue is afforded by 0.1 g of 

 folic acid for each 10 g of crude inhibitor, the inhibition index is greater 

 than 100. 111 



Chicks on a folic acid-deficient diet develop symptoms which include 

 slow growth, poor feathering and low hemoglobin content of the blood. 



