THE CELL MEMBRANE AS A SITE FOR MERCURIAL ACTION 893 



in heavy metal ion inhibitions as an introduction. Although many workers 

 have considered the effects of heavy metal ions on membranes, the concepts 

 presented here will be mainly those of Rothstein and his group at Rochester, 

 since they have been actively engaged for over 10 years in studying this 

 problem. Although much of the evidence is based on work with copper, 

 molybdate, and uranyl ions, and the theory is meant to apply to heavy 

 metal ion action in general, Hg++ has been used frequently and it is im- 

 possible to discuss the effects of the mercurials on cells and tissue without 

 considering this aspect of their actions. The basic concepts of Rothstein 

 (1959) may be summarized as follows. (1) The cell membrane is exposed 

 directly to the heavy metal ions in the medium and is that part of the cell 

 which reacts initially when the heavy metal ions are added. Ligand groups 

 at the surface or within the membrane will combine with the heavy metal 

 ions as they diffuse, and hence the membrane will experience the first ef- 

 fects, and certain changes in cellular metabolism or function may at this 

 time relate to a selective membrane action. (2) The cell membrane usually 

 presents a barrier to the penetration of the heavy metal ion into the cell 

 and thus protects the cytoplasmic enzymes. (3) Nonenzymic or nonfuc- 

 tional ligand groups in the membrane or within the cell combine with the 

 heavy metal ions and thereby protect the active sites by reducing the 

 amount of heavy metal ion which is free to react. (4) As a result of the 

 second and third postulates, enzymes within cells are less readily attacked 

 by metal ions than when they are isolated from the cells. (5) As a result 

 of the first statement and the fourth deduction, it would be likely that the 

 major site of heavy metal ion action on cells and tissues is often the cell 

 membrane, rather than the enzyme and metabolic systems within the cell. 

 (6) The most important active sites in the membrane are enzymes or other 

 components involved in the transport of substances across the membrane. 

 Much of the toxicity would therefore be due to interference with the move- 

 ments of substrates or ions into or out of the cell. 



Glucose Uptake and Respiration of Diaphragm Muscle 



The uptake of glucose by rat diaphragm is almost completely abolished 

 within 20-30 min by 0.2 milf Hg++, but the respiration is not affected be- 

 fore 30 min and is inhibited only 30% maximally after 2 hr (Fig. 1-12-31) 

 (Demis and Rothstein, 1955). It requires 2 mM Hg++ to inhibit the res- 

 piration 90% and this occurs after 1.5 hr. Thus glucose uptake is depressed 

 much more rapidly and is more sensitive than respiration by at least a 

 factor of 10. These results might imply that Hg++ acts initially on the mem- 

 brane to block glucose transport, and later on intracellular respiratory sys- 

 tems; depression of glucose uptake does not in itself inhibit respiration since 

 the latter is dependent on endogenous substrate. Of some confirmatory evi- 

 dence is the fact that cysteine will reverse the inhibition of glucose uptake 



