522 2. ANALOGS or enzyme reaction components 



intraperitoneally for 5-6 days) is lowered and, in contrast to normal or 

 thiamine-deficient animals, administration of glucose does not raise it (see 

 accompanying tabulation) (de Caro et al., 1954). There is thus an inhibition 



of the total oxidation of carbohydrate, which can be directly attributed to 

 a block in pyruvate oxidation; however, it is difficult to explain the greater 

 effect in the diet-deficient animals. The only work showing an impairment 

 of transketolase function is that of Wolfe (1957). Rats deprived of thiamine 

 or given oxythiamine show a depression of the pentose-P pathway in the 

 erythrocytes, pentose accumulating, whereas pyrithiamine produces no 

 changes in transketolase activity even when the animals are paralyzed. 



Some interference with amino acid metabolism by thiamine analogs, me- 

 diated through changes in the utilization of the a-keto acids, might be ex- 

 pected, but little study of this has been made. Pyrithiamine inhibits the 

 formation of aspartate and asparagine from glutamate in germinating Pha- 

 seolus seeds and there is an accumulation of ammonia, possibly due to the 

 lack of oxalacetate (Sivaramakrishnan and Sarma, 1954). These effects can 

 be attributed to a reduction in a-ketoglutarate oxidase. Oxythiamine and 

 pyrithiamine both inhibit the growth of Vibrio cholera and lead to the accu- 

 mulation of alanine, aspartate, and glutamate. The effects on the levels of 

 such amino acids will depend to a great extent on the pattern of metabolism, 

 i.e., on the over-all direction of transamination reactions. 



Effects on Thiamine-PP Synthesis 



Pyrithiamine has been found to inhibit thiamine kinase from chicken 

 blood (Woolley, 1950 a), rat liver (Eich and Cerecedo, 1954; Mano and Ta- 

 naka, 1960), rat intestine (Cerecedo et al., 1954), and pigeon liver (Koedam, 

 1958), and the inhibition appears to be competitive with thiamine. This in- 

 hibition is fairly potent: When the ratio pyrithiamine/thiamine is 1 the in- 

 hibition is around 50%, at a ratio of 5 it is 75%, and at a ratio of 10 it is 

 90% in rat liver and intestine (thiamine concentrations 0.01-0.1 raM). On 

 the other hand, oxythiamine inhibits thiamine kinase much less strongly 

 or not at all when present in similar ratios to thiamine (Eich and Cerecedo, 

 1954; Cerecedo et al, 1954; Koedam, 1958; Mano and Tanaka, 1960). The 



