MUTAGENS OF POTENTIAL SIGNIFICANCE 



207 



5-1 



E 



Figure 28B. Blood levels in man after caffeine administration. 

 Coffee given repeatedly to 5 subjects as shown. Symbols have 

 the same meaning as above. 



that caffeine is almost completely metabolized. Practically none can 

 be recovered in the urine, at least no more than 2 to 3 per cent of the 

 amount ingested, but the major fraction of the ingested caffeine appears 

 as metabolites. There are two kinds of metabolic alteration: removal 

 of methyl groups, first from position 3, then from position 7; and also 

 oxidation at position 8 (Fig. 27) . The end result is a series of pro- 

 gressively demethylated xanthines, and another series of uric acid 

 derivatives in which more or less demethylation has occurred. The 

 principal metabolite of caffeine is 1 -methyl uric acid, in which only 

 the methyl group in position 1 remains, and position 8 has been 

 oxidized. Minor metabolites include 1-methyl xanthine and 3-methyl 

 uric acid, and traces of the other possible compounds. The pattern of 

 metabolism of theobromine is somewhat different, principally in that 

 a significant amount of theobromine itself is excreted. But I want to 

 point out again that the caffeine levels we are looking at in these 

 figures represent caffeine itself and not metabolites of caffeine. 



Freese: How have these metabolites been measured? I mean, is it 

 sure that these are the only ones? 



Goldstein: I think it is quite sure, Ernst. These metabolites were 

 measured by a good paper chromatography separation of products in 

 the urine, and quite well identified quantitatively. This was done, I 



