220 G. Nichols, jr. 



related directly to enzyme activity through inhibition — competitive or non-com- 

 petitive — or activation by degradation of a zymogen or polymerization of inactive 

 subunits. When enzyme availability is considered, relative rates of synthesis and 

 destruction which must depend in turn on the availability and activity of still other 

 enzymes offer potential controls very reminiscent of the factors controlling the 

 availability of membrane carriers. As one looks further the potential importance of 

 membranes reappears in even more direct form. Potent enzymes may be effectively 

 isolated from their substrates except under special conditions by impermeable mem- 

 branes as is the case in lysosomes. Moreover, the critical dependence of the com- 

 position of the whole internal environment in which enzymes act on the activity of 

 membrane transport systems may be cited as an even more dramatic example of the 

 potential interplay of one area of action on another. 



The third area of potential hormone action has been termed "transfer" of genetic 

 information but could equally have been designated "control of nuclear metabolism". 

 In any case its inclusion is a direct outgrowth of the notion that the rates of bio- 

 synthesis and destruction of membrane carriers, membranes, structural proteins and 

 metabolic energy depend fundamentally on the availability of suitable enzymes 

 which in turn implies not only synthesis of the proper enzyme proteins but proper 

 guidance and integration of the entire system as well — considerations which make 

 the metabolic processes by which cell nuclei control protein synthesis highly likely 

 targets for hormonal influence. Once this view is entertained numerous sites for 

 hormone action suggest themselves ranging from selection of the DNA "message" to 

 be "transcribed" through the steps involved in the biosynthesis, release, transport, 

 utilization and destruction of "messenger" RNA. Each of these steps, it must be 

 remembered, probably Involves In Its turn enzymes and thus protein synthesis etc. — 

 even the veiling and unveiling of genetic loci on DNA strands may depend on 

 protein formation and interaction If Jacob and Monod's (1961) concepts of repres- 

 sion and de-repression can be proven applicable in animal systems. Finally, the fac- 

 tors which affect transfer of substances across membranes, in this case the nuclear 

 membrane, again must be considered. Thus when this third area of possible hormone 

 activity is reviewed the same handful of mechanisms seem to be the ones available for 

 mediation of hormone influences on metabolism. 



These thoughts lead inevitably to the view that only 3 modes of action of 

 hormones at the molecular level seem possible — effects on membrane structure 

 yielding changes in permeability; direct inhibition or activation of enzyme activity; 

 and effects on the cell nucleus resulting In qualitative or quantitative changes in the 

 transcription of genetic information which are reflected by changes In messenger 

 RNA and protein synthesis. The next step is to see how well present evidence of 

 hormonal action at the molecular level appears to fit these predictions. The few 

 examples which follow have been selected from the many available to illustrate that 

 hormone effects on each of the 3 basic mechanisms postulated have now been demon- 

 strated. 



The first of these ■ — a direct effect on membrane structure and permeability — is 

 well Illustrated by the Increase in the bulk flow of water across the toad's bladder 

 Induced by vasopressin. Fig. 3 taken from Hays and Leaf's (1962) original paper 

 clearly Indicates that the flux of water across this membrane under a variety of 

 osmotic gradients Is several fold greater when vasopressin is added in vitro, appar- 



