TYROSINE METABOLISM 319 



sues are not known, but it was demonstrated that a-methyldopa does not 

 penetrate into brain. In the second place, the decarboxylases from the var- 

 ious tissues may have different susceptibilities to the analogs, as we have 

 noted above. Perhaps cardiac decarboxylase is resistant to a-methyldopa 

 while the renal enzyme is more sensitive. 



(2) Monoamine oxidase inhibitors were administered during norepineph- 

 rine depletion, and norepinephrine levels immediately rose (Hess et al., 

 1961). It was concluded that "biosynthesis of norepinephrine can still 

 occur in animals treated with or-methylamino acids." All these results 

 mean is that inhibition of the decarboxylase was not complete. In any 

 sequence 



AillB^C 



an inhibition of (1) will lower B and an inhibition of (2) will raise B (see 

 Chapter 1-7). 



(3) It is stated that the decarboxylase step is the most rapid in the 

 over-all sequence and therefore cannot be rate-limiting (Hess et al., 1961). 

 The conclusion was that the decarboxylase must be inhibited very strongly 

 for any effect to be observed. First, it is very difficult to establish that 



very very 



Tyrosine — > dopa — > dopamine — > norepinephrine 



sloiv fast slow 



these are the relative rates of the reactions in vivo, where the concentra- 

 tions and states of the enzymes are quite different than when isolated from 

 the cells. Second, the rate of formation of norepinephrine in a steady state 

 is controlled by the first reaction (or a previous reaction) since these 

 reactions are virtually irreversible. An inhibition of dopa decarboxylase 

 will not alter the rate of norepinephrine formation as long as a steady 

 state is maintained; the concentration of dopamine will also be unchanged 

 in the steady state. However, it has been demonstrated that dopamine 

 concentration falls, indicating that a departure from a steady state has 

 occurred. One must also consider the other possible metabolic pathways 

 for dopamine (e.g., oxidation and 0-methylation), since this is a divergent 

 sequence. A certain depression of the decarboxylation need not be reflected 

 in the same depression of norepinephrine formation, even under nonsteady- 

 state conditions; the latter can be either greater or less than the inhibition 

 of dopamine formation. In the case of serotonin formation, the decar- 

 boxylation is the last step, and whether it will be inhibited or not will 

 depend on the degree to which 5-hydroxytryptophan concentration can 

 rise to overcome the block. In any event, it has been shown that the 

 in vivo inhibition of decarboxylase by these analogs can be very high 

 and sometimes complete. 



