76 The Chemistry of the Injured Cell 



vented through deficiency of choline, neutral fat is produced in 

 excess and this accumulates within the cell because it is not so 

 easily metabolised as lecithin. Judah and Rees showed that CC1 4 

 induces excessive phosphatide acid production in liver cells so that 

 even optimal supplies of choline are insufficient for the synthesis of 

 lecithin and much of the diglyceride is diverted to neutral fat. This 

 abnormality of metabolism sets in at an early stage of CC1 4 intoxica- 

 tion long before the mitochondria are damaged. Poisoning with 

 carbon tetrachloride may thus make the cell relatively deficient 

 in choline; the fatty degeneration that results could well be the 

 outcome of a lack of lipotropic factor. 



The necrosis of carbon tetrachloride poisoning is also being 

 studied in our laboratory. The anti-histamine drug, Phenergan 

 (promethazine HC1) , greatly lessens the severity of the mitochon- 

 drial damage and necrosis, but leaves the fatty change unchecked 

 (Rees, Spector and Sinha, 1961) . It seems that fatty degeneration 

 is a manifestation quite apart from mitochondrial damage, necrosis 

 and the associated escape of enzymes from these cells. Adrenalec- 

 tomy acts similarly to Phenergan. These findings suggest that both 

 necrosis and mitochondrial damage are the outcome of a funda- 

 mental alteration of cell permeability which may even be second- 

 ary to disruption of normal electrolyte movements. 



Thioacetamide 



Thioacetamide has achieved some importance as a fungicide 

 for the prevention of decay in oranges. In high doses it induces 

 centrolobular necrosis in the liver of rats (Gupta, 1956) . Workers 

 in our laboratory have shown that it inhibits the respiratory me- 

 tabolism of liver cells and their mitochondria, an effect which is 

 associated with a high concentration of calcium ions in those cells 

 (Gallagher et ah, 1956) . If the Ca ions are inactivated by the addi- 

 tion of versene, respiration of liver homogenates and mitochondria 

 will go on normally. Since calcium is a potent inhibitor of respira- 

 tion and an uncoupler of oxidative phosphorylation in vitro, the 

 inhibition of respiration in thioacetamide poisoning may be 

 secondary to accumulation of calcium in the cell. 



A further interesting disturbance can be traced to thioaceta- 



