MECHANISM OF PARATHYROID HORMONE ACTION 585 



If the mechanism of action of a hormone on one tissue is due to 

 a specific metaboUc alteration, and if that same hormone has an- 

 other physiologic action on another tissue, we should make an at- 

 tempt to explain the second action in terms of the same biochemical 

 mechanism that was suggested for the first action. The effect of the 

 parathyroid hormone on the kidney is related to the excretion of 

 phosphate. Without going into the details of the renal handling of 

 phosphate, we might suggest that possibly the ionic form of the 

 phosphate is important. An increased local production of carbonic 

 acid would alter the ratios of the different forms of phosphate to 

 one another; the major change would be a shift from the monohy- 

 drogen form to the dihydrogen form. 



The bulk of present evidence is in agreement concerning the 

 necessity of cellular metabolism for dissolving minerals of bone. 

 Much of this evidence suggests that parathyroid hormone increases 

 the rate of some part or parts of cellular metabolism in bone. It 

 seems more reasonable that the effect of the hormone on the struc- 

 ture of bone is mediated by an end product of this metabolism than 

 by an intermediate product in the metabolic process. However, the 

 need for active metabolism does not necessarily mean that the 

 prpcess of dissolution requires energy. 



It appears that the activity of the hexose monophosphate shunt 

 is not related to the effect of the hormone, so we shall concentrate 

 on the glycolytic and Krebs pathways. The marked accumulation of 

 lactate, even under aerobic conditions, suggests that the limiting 

 step in the sequence occurs after pyruvate. Since we found that the 

 parathyroid hormone increases CO2 production with pyruvate-2-C^^ 

 as the substrate but not with citrate-l,5-C^^ (Cohn and Forscher, 

 1961), and with lactate-1-C^^ as substrate but not with succinate- 

 1,4-C^^ ( Cohn, 1962 ) , we might narrow our attention to the sequence 

 between pyruvate and citrate. Raisz and co-workers (1961) also did 

 not find an effect on CO2 labeling with acetate- 1-C^^ as substrate; 

 but, in their experiments, glucose was present in high concentrations. 



The CO2 production relevant to the effect of parathyroid hormone 

 requires the operation of the Krebs cycle. We suggest that the rate 

 of operation of the Krebs cycle is controlled by the entry of me- 



