74 The Chemistry of the Injured Cell 



might exert some physical action on the mitochondrial membrane 

 rendering it more permeable to co-factors, especially DPN, and 

 thus leading to failure of respiration and cell death. About the same 

 time, Dianzani (1954) found that CC1 4 uncouples oxidative phos- 

 phorylation, increases the ATP-ase activity, induces loss of pyridine 

 nucleotides and cytochrome c and diminishes the ATP content of 

 the liver. He suggested that CC1 4 and other hepatotoxins destroy 

 mitochondrial function and so deprive the cell of ATP and that 

 this leads to a secondary failure of fatty acid activation. Dianzani 

 recorded biochemical disturbances before fat accumulates in the 

 liver and attributed the increase in fat to failure of fatty acid oxida- 

 tion (1957) . His observations were made on livers twenty-four 

 hours or more after exposure to carbon tetrachloride, at a time 

 when structural damage is pretty severe. 



Recently more attention has been given to the fatty change that 

 characterises liver cells in the early stages of CC1 4 intoxication. In 

 vivo and in vitro studies show that CC1 4 reduces the 2:4 dinitro- 

 phenol-activated ATP-ase system and activates the Mg-ATP-ase- 

 system; these events unfold side by side with loss of a-ketoglutarate 

 and glutamic oxidase activity (Recknagel and Anthony, 1959). 

 Such results suggest some mitochondrial disorganisation. But the 

 total liver fat level is twice normal long before the mitochondria 

 are apparently damaged which means that the cellular fat increases 

 independently of impaired mitochondrial function. Moreover, in 

 adrenalectomised animals twenty hours must elapse before the fatty 

 change develops after exposure to CC1 4 and mitochondrial function 

 is still normal. At this time the concentration of CC1 4 in the liver 

 is low (Recknagel, Stadler and Litteria 1958) . 



Finally, protection of mitochondria against the action of CC1 4 

 is given by a variety of compounds, e.g. sulphaguanidine and 

 phenergan; both protected and unprotected livers lose their cyto- 

 plasmic basophilia and glycogen, and accumulate fat, but the mito- 

 chondria remain unchanged in the protected liver (Rees, Spector 

 and Sinha, 1961). Hence it seems likely that CC1 4 induces two 

 separate changes in the liver cells; (1) fatty degeneration and (2) 

 mitochondrial damage. 



There seems to be little doubt that CC1 4 affects the integrity of 



