DIFFERENTIAL EFFECTS IN WHOLE ANIMALS 483 



in greater amounts in certain cell layers and is found to be very high in the 

 molecular layer of the cerebellar cortex. The distribution of glutamic 

 decarboxylase (Albers and Brady, 1959) is equally inhomogeneous but 

 different from the previous enzyme: lumbar spinal cord, 15, pons and me- 

 dulla, 34; motor cortex, 62; cerebellum. 79; thalamus, 85; hypothalamus, 

 96; and midbrain. 100. Cytochrome oxidase and dipeptidase have been 

 determined in the human central nervous system and the relation of the 

 former to the different respiratory rates has been discussed (Pope et at., 

 1957). The distribution of eight enzymes involved in glucose metabolism 

 and two cycle enzymes has been studied in the cerebellum (Robins et al., 

 1957). The distribution of certain dehydrogenases between the gray and 

 white matter of human brain perhaps indicates a concentration of these 

 enzymes in the synaptic regions (Tyler, 1960). Thus lactate dehydrogenase 

 concentrations are 3.2-9.2 in gray matter and 2.9-4.5 in white matter, 

 while malate dehydrogenase concentrations are 11.8-23.1 in gray matter 

 and 10-15 in white matter, the figures being units per milligram of tissue 

 weight. All of these results indicate strongly that the metabolic patterns 

 of the regions within the central nervous system are sometimes quite dif- 

 ferent. Here one has, then, metabolic differentiation in one type of tissue, 

 so that variations are to be visualized not only between different tissues 

 but between the histologically and functionally separable regions or cells 

 of a single tissue. 



When an inhibitor combines with an enzyme in an irreversible or pseudo- 

 irreversible fashion, the relative effects on the tissues throughout the body 

 will in part depend on the concentrations of enzyme in these tissues, the 

 fractional inhibition being inversely related to the amount of enzyme (see 

 Chapter 3). When the response of tissue function is being measured, however, 

 the relative effects will be related also to the dependency of the function 

 on the particular enzyme or metabolic pathway inhibited, since the tissue 

 experiencing the greatest metabolic inhibition is not necessarily the one 

 being most functionally disturbed. 



The so-called branching points in metabolism may be of special impor- 

 tance in the different responses of tissues to inhibitors. These branching 

 points may be the source of divergent chains or bilinear shunts. Some tis- 

 sues are undoubtedly resistant to certain inhibitors because they possess 

 a pathway that circumvents the locus of block. Pyruvate is one of the pri- 

 mary branching sites in the cell, since often it may be metabolized in sev- 

 eral different ways. Pyruvate in animal tissues can enter the cycle in two 

 different ways; the condensation with CO., to form dicarboxylic acid which 

 increases the amount of cycle intermediates and allows synthesis, and it 

 can also be oxidatively decarboxylated to acetyl-CoA which can be used as 

 an energy source in the cycle. Injection of DL-alanine-2-C^* into rats and 

 the determination of the labeling in L-glutamate indicates the relative 



