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L. J. MULLIXS 



Diameter of Site 



Enzyme 



Fig. 8. The suggested interspace site distribution for DDT-sensitive organisms is 

 shown as curve 2, while curve 4 represents the distribution for resistant organisms. 

 The addition of a synergist changes curve 2 to 1, and curve 4 to 3. DDT sites are 

 shown by the vertical bar, and enzyme sites by the area to the right of the dotted 

 vertical line. 



The action of certain non-insecticidal homologs of DDT is helpful in analyz- 

 ing the relationship between enzyme and receptor. Thus, 2,2 bis (p-chlor- 

 phenyl) 2 hydroxy ethane synergizes the action of DDT on resistant flies only, 

 and is an inhibitor of the enzyme (Moorefield and Kearns, 1955). Such an 

 action is predictable if the substance is an anesthetic that, because it occupies 

 more than just the free volume in an interspace, shifts the interspace mean 

 size to smaller values, as shown in Fig. 8, as well as reducing the number of 

 sites that are too large for DDT (enzyme sites). Substances that have no sub- 

 stituent of high electron density and are small enough to penetrate in mam- 

 different orientations like diphenylhydroxymethane neither synergize the 

 effects of DDT nor inhibit the enzyme at the concentrations studied, while 

 substances like bis (p-chlorphenyl) hydroxymethane do apparently have 

 enough binding strength to inhibit the enzyme but do not occupy much more 

 than the free volume of an interspace and therefore do not change the inter- 

 space distribution. Because all the inhibitors are about 10 3 more water soluble 

 than DDT it is impossible to estimate relative membrane concentrations but 

 even in their highest concentrations, inhibitors inactivate only 70% of the 

 DDT-ase. 



The preceding discussion has suggested that the process of obtaining organ- 

 isms resistant to DDT selects from a population those individuals with a 

 different membrane structure. The conventional notion that the presence of 

 an enzyme detoxifying DDT is responsible for DDT resistance is to be con- 

 trasted with the view that the enzyme is a consequence of a membrane struc- 

 ture that is not sensitive to DDT. It is extremely difficult to distinguish, 

 experimentally, between these possibilities because they amount to saying that 

 the receptor is somewhat more selective in its stereochemical requirements 



