582 5. QUINONES 



to the binding by serum discussed in the previous section. One would 

 certainly expect most quinones to enter cells readily since they are un- 

 charged over the physiological pH range, although some hydroxy naphtho- 

 quinones are ionized to varying degrees (see page 428), and they possess 

 lipophilic regions of some extent, and indeed much work has indicated a 

 rapid action on cells. However, evidence from rates of action on cellular 

 functions is not good since in most instances we do not know if the site of 

 action is really intracellular. 



The effects of pH on the activities of the polyphenols are related mainly 

 to the rates at which oxidation to quinones occurs, so that, as we have dis- 

 cussed in several places, the hydroquinones usually act more rapidly and 

 to a greater degree as the pH is raised. There is no evidence that rate of 

 penetration or ionization of the phenols is involved. Since most of the 

 quinones do not ionize in the physiological pH range, it is likely that any 

 pH effects observed must be due to factors other than variation in a pene- 

 trable form. The effectiveness of most quinones on cellular processes de- 

 creases as the pH is raised: menadione at 0.006 mM has no effect on Achro- 

 mobacter luminescence at pH 7.3 but inhibits completely at pH 4.5 (McElroy 

 and Kipnis, 1947), phthiocol is less effective in stimulating algal respira- 

 tion as the pH increases (Gaffron, 1945), various quinones cease to affect 

 the phosphate uptake of yeast when the pH is raised (Hoffmann-Ostenhof 

 and Kriz, 1948), and naphthoquinones are less potently antibacterial at 

 pH 7.3 than at 6.0 (Marrian et al., 1953). The only exception to this is the 

 moderately greater inhibition of glycolysis in ascites carcinoma cells by 

 25-benzoquinone as the pH is raised from 6.0 to 7.3 (Holzer et al, 1956). 

 The respiration of yeast is inhibited by toluquinone to approximately the 

 same degree at all pH's from 5.2 to 8.0, although there may be a slight 

 maximum around neutrality (Hoffmann-Ostenhof and Kriz, 1949 b). Sev- 

 eral factors must be involved in these pH effects, including the alterations 

 in membrane permeability, changes in the rate of reaction with SH of NHg 

 groups, the stability of the quinones, and the variation in the redox poten- 

 tials with pH. In any event, the data from pH studies provide no direct 

 evidence for evaluating rates of penetration. 



The general stability of the quinones, the reactions with thiols and 

 amines, and the oxidation-reduction reactions occurring nonenzymically 

 and enzymically have been previously discussed (page 434), but in ad- 

 dition to these the quinones may undergo a variety of changes following 

 administration to an animal or introduction into cell suspensions. The 

 benzo- and naphthoquinones will be taken up separately here because their 

 metabolisms generally differ. Polyphenols are conjugated with various 

 groups in the liver and are partly excreted in these forms; the fate of the 

 quinones is often similar since they can be reduced in the tissues. Thus 

 administration of p-benzohydroquinone to dogs leads to the appearance 



