14 The Chemistry of the Injured Cell 



action and phenergan and chlorpromazine might exert a similar 

 effect, although there are alternative explanations for the action of 

 these phenothiazines (see below) . It would have to be assumed that 

 auto-oxidation would destroy the specificity of the ion-binding 

 groups but such groups could form part of both a membrane trans- 

 port system and an internal ion-binding matrix. In view of the pro- 

 tective effect of vitamin E and phenergan in dietary liver necrosis 

 and of phenergan in hepatic necrosis induced by carbon tetrachlor- 

 ide and thioacetamide (Rees, Spector and Sinha, 1961), it is 

 possible to postulate auto-oxidation as a potential pathological 

 mechanism in conditions other than vitamin E deficiency. Conway 

 (1955) has suggested that ion transport may depend upon oxidation- 

 reduction reactions in the cell membrane, with electron transport 

 through iron-containing enzymes. The theory postulates that when 

 the complex is reduced, there is specific absorption of sodium or 

 potassium ions on to the negative charge thus produced. With oxi- 

 dation, the ion is released. Conway's theory has been challenged but 

 it is easy to see that his hypothesis is consistent with that based on 

 the actions of anti-oxidants in cell injury associated with vitamin 

 E deficiency. Although acute disturbances may occur in the pres- 

 ence of normal metabolism it is abundantly clear that sustained 

 maintenance of normal ionic gradients depends directly or in- 

 directly on energy transformations within the cell. This is true 

 whether the important mechanisms are ionic pumps or ion-binding 

 matrices. It is also known that ionic gradients do not necessarily 

 depend on ATP, the major source of stored energy, itself. Some 

 recent work of Judah ( 1 960) indicates that at least one of the energy 

 transforming reactions closely concerned with electrolyte metabol- 

 ism may be the phosphorylation and dephosphorylation of cellular 

 phosphoproteins. Thus certain phenothiazines, notably phenergan 

 (promethazine HC1) inhibit the incorporation of phosphate into 

 phosphoprotein in parallel with similar inhibition of electrolyte 

 movement. Should further work confirm the importance of the 

 phosphoprotein system and the impression of its nature now ob- 

 taining, it would seem that its characteristics favour an ion-binding 

 matrix (perhaps the phosphoproteins itself) rather than an ionic 

 pump. 



