The mode of action of pyrithiamine as an inductor of thiamine deficiency

Abstract

1. 1. A study was made of the development of thiamine deficiency in pigeons by feeding the antagonist pyrithiamine together with thiamine, as a supplement to a diet rich in carbohydrate. This deficiency was compared to that induced in the traditional manner by feeding a thiamine-free carbohydrate-rich diet.

2. 2. In both cases a strong decrease of the thiamine pyrophosphate content of various tissues was observed, as well as a decrease in anaerobic formation of acetoin and consumption of pyruvate by homogenates of breast and heart muscle. In most respects there is a close resemblance between the two types of deficiency.

3. 3. The only differences were: (a) after giving pyrithiamine, thiamine pyrophosphate decreases as rapidly in brain as it does in other organs, while this tissue is slower in losing its thiamine pyrophosphate when thiamine is withheld from the diet; (b) after giving pyrithiamine there is a much higher incidence of opisthotonus on the carbohydrate-rich diet than after withholding thiamine. However, it is not yet possible to establish a causal relationship between the occurrence of opisthotonus and the disappearance of thiamine pyrophosphate from the brain.

4. 4. Pyrithiamine strongly inhibits the phosphorylation of thiamine by rat-liver thiaminokinase in vitro.

5. 5. It seems most likely that pyrithiamine will also act in vivo by inhibiting the phosphorylation of thiamine to thiamine pyrophosphate. This gives an adequate explanation of all phenomena observed.

6. 6. There is no necessity for postulating a second specific function of thiamine in the brain, not requiring phosphorylation to thiamine pyrophosphate, a function upon which pyrithiamine would exert a specific action.