774 15. EFFECTS OF VARIOUS FACTORS ON INHIBITION 



unstable than any of its constituent parts. Thus proteins are much more 

 unstable at elevated temperatures than are the amino acids and, likewise, 

 the cell is more unstable than the enzymes or structural protein complexes 

 as the temperature is raised above the normal levels. Most mammalian cells 

 are seriously disturbed or damaged when the temperature is increased more 

 than 50 above the physiological value. This instability is due in part to 

 structural alterations but, more importantly, to the imbalance in the over- 

 all metabolic i^attern. Occasionally it is possible to isolate experimentally 

 some part of the cell metabolism and test its response to inhibition and 

 changes in the temperature, but one must beware of oversimplification, 

 inasmuch as the various activities of the cell are so closely related. For 

 example, it might seem that the Ijioluminescence system would provide a 

 relatively simple cellular activity to measure, but here one is not only deal- 

 ing with the enzymes and pathways involved in the production of the ra- 

 diation, but perhaps also with the systems that supply the energy (respi- 

 ration and oxidative phosphorylation), the systems regulating the concen- 

 trations of enzymes and coenzymes, and possibly with structural factors 

 upon which the organization of the energy flow depends. Despite the in- 

 herent complexity of all cellular behavior following temperature changes, 

 the problems are not insuperable if they are approached with a full aware- 

 ness of this complexity and a knowledge of the temperature dependency 

 of the component systems. 



The effects of reduced temperatures on tissues and organs have recently 

 become important as a result of the widespread use of hypothermia in sur- 

 gery. The responses of the tissues to anoxia, drugs, and metabolic inhibitors 

 at these low temperatures are largely unknown as yet, but must eventually 

 be determined before we can thoroughly understand the hypothermic state 

 and apply it more widely to medical problems. One might say with some 

 justification that there is here a new field of low-temperature bioche- 

 mistry, physiology, and pharmacology, about whicli essentially nothing is 

 known at present, relative to our knowledge obtained under normothermic 

 conditions. 



Factors Related to Inhibition at the Cellular Level 



When the degree of inhibition produced by a certain concentration of 

 inhibitor on a metabolic or functional activity of a cellular system is found 

 to vary with the temperature, there may be many contributing factors in 

 addition to the primary changes in the inhibition at the enzyme level. In 

 other words, a cellular system cannot l)e treated as a collection of indepen- 

 dent enzyme units lacking spatial organization. The actions of an inhibitor 

 on a cell may be conditioned by a variety of factors imposed by the total 

 structural and metabolic pattern, some of which have been discussed in 

 Chapter 9, and these factors may be more sensitive to temperature changes 



