FRANK H. JOHNSON 281 



fected (Fisher and Steam, 1942). The same results could occur, how- 

 ever, if two or more different equilibria, characterized by different 

 ratios of combining molecules, and very likely also by different heats 

 and entropies of reaction, were established with the same enzyme 

 system. In living cells it is difficult to distinguish between two such 

 possibilities. Action of the drug through multiple equilibrium reac- 

 tions with a single enzyme is the simpler explanation, however, and 

 there is convincing evidence that urethan catalyzes the thermal de- 

 naturation of tobacco mosaic virus through more than a single reac- 

 tion with this protein (vide infra). The denaturation of tobacco 

 mosaic virus in urea at 0° to 40° C also involves multiple reactions 

 between urea and the protein ( Lauffer, 1943 ) . 



Catalysis of Irreversible Protein Denaturation by Narcotics 



On general considerations it would appear likely that the same 

 drugs which promote a reversible denaturation of enzymes or other 

 proteins would also under appropriate conditions be found to promote, 

 or catalyze, an irreversible denaturation of the same proteins. Urethan, 

 in fact, has been shown to promote the denaturation of egg albumin 

 and serum proteins at room temperature ( Hopkins, 1930 ) . In concen- 

 trations of physiological interest, urethan catalyzes the destruction of 

 the bacterial luminescent system, at a rate dependent upon the con- 

 centration of the drug at a given temperature (Fig. 11). As a result, 

 the initial inhibition, just after adding the drug, increases progres- 

 sively with time. There are numerous other instances of such a dual 

 action of a drug, which is in marked contrast to the action of others, 

 e.g., of sulfanilamide on bacterial luminescence, wherein the inhibi- 

 tion remains essentially constant with time. The inhibition of respira- 

 tion of rat brain slices by phenobarbital, for example, indicates a dual 

 action similar to that of urethan on bacterial luminescence (cf. analy- 

 sis of the data of Jowett (1938) in Johnson, Eyring, and Polissar, 

 1954). 



Pressure Retardation of Narcotic-Catalyzed Denaturation 



On the basis of the foregoing observations, it would be expected 

 that the irreversible denaturation of one or more enzymes essential to 

 bacterial luminescence, in the presence of certain narcotics, would be 



