510 R. E. HANDSCHUMACHER AND A. D. WELCH 



manner or limit by this blockade the synthesis of additional DNA required 

 for reproduction. 



Another facet of the biological effects of bromouracil was seen in the 

 accumulation of significant amounts of 6-methylaminopurine in the DNA 

 of E. coli, m an effect also produced by thymine deficiency or by inhibition 

 with 5-aminouracil. The relationship of this abnormal purine and the re- 

 placement of thymine by bromouracil in the fine structure of the resultant 

 DNA will be important to consider as more information accrues concern- 

 ing the functional role of this macromolecule. Data already at hand would 

 suggest that such incorporation causes an increased rate of mutation in 

 E. coli (exposed to iodouracil) 438 and in its T-even phages, 429 particularly 

 when incorporation of the analog is enhanced by limitation of the synthesis 

 of thymine de novo with sulfanilamide. The production of antibodies in 

 slices of spleen is blocked by bromodeoxy uridine, an effect which is pre- 

 vented by thymidine. 439 



Degradation of the 5-halogenated pyrimidines appears to follow a similar 

 course to that for uracil or thymine. Following administration of bromou- 

 racil to human subjects or to rodents, one of the urinary excretion products 

 appeared to be /3-ureidopropionic acid. 440 It is believed by some that initial 

 formation of the dihydropyrimidine, a reaction demonstrated in vitro for 

 bromouracil and iodouracil, 441 is followed by a dehydrohalogenation which 

 yields uracil and, respectively, either bromide or iodide ions. 442 The uracil 

 is then metabolized in a normal fashion. A large number of substituted 

 halogenated derivatives have been studied in vivo and in general the results 

 have confirmed this hypothesis. 



Biological studies on chloro- and bromocytosine and their corresponding 

 ribonucleosides 443 and deoxyribonucleosides 444 have not been as extensive. 

 It would appear that a portion of the activity of the ribonucleosides may 

 be attributed to deamination to the corresponding uridine analogs. 445 How- 

 ever, the ribonucleosides are more potent inhibitors of the growth of a 

 pyrimidine-requiring mutant of Neurospora, a circumstance which is par- 

 ticularly marked when growth is supported by cytidine. 443 



438 D. Luzzati, Comp. rend. acad. sci. 245, 1466 (1957); cf. footnote 7, Matthews. 



439 R. W. Dutton, A. H. Dutton, and J. H. Vaughan, Federation Proc. 18, 219 (1959). 



440 H. B. Pahl, M. P. Gordon, and R. R. Ellison, Arch. Biochem. Biophys. 79, 245 

 (1958). 



441 S. Grisolia, J. Caravaca, S. Cardoso, and D. P. Wallach, Federation Proc. 16, 

 189 (1957). 



442 H. W. Barrett and R. A. West, J. Am. Chem. Soc. 78, 1612 (1956). 



443 T. K. Fukuhara and D. W. Visser, J. Am. Chem. Soc. 77, 2393 (1955). 



444 I). M. Frisch and D. W. Visser, J. Am. Chem. Soc. 81, 1756 (1959). 



445 S. S. Cohen and H. D. Barner, J. Biol. Chem. 226, 631 (1957). 



