78 The Chemistry of the Injured Cell 



that failure to maintain the proteins of the cell in general, or to 

 synthesise one or more specific protein involved in cell metabolism 

 may be the cause of the "biochemical lesion" that ultimately leads 

 to cell death. According to Miss Margot J. Bailie (Thesis, 1959), 

 dimethylnitrosamine causes leakage of DPN from mitochondria 

 so that the cell loses its stores of this compound. Such an action 

 recalls the "ageing" of mitochondria whereby they no longer con- 

 centrate certain ions after storage at low temperature. "Aged" mito- 

 chondria sustain a loss of nucleotides, including DPN, and ac- 

 cumulate water (Ernster and Lindberg, 1958) . At the same time, 

 DPN-linked oxidations and oxidative phosphorylation are in- 

 hibited or lost. More recent work by Farber and Magee, as yet un- 

 published, suggests an alternative mode of action for the action of 

 this substance on liver cells. Thus the injection of dimethylnitro- 

 samine (DMN) into rats is followed by the appearance of 7-methyl- 

 guanine in the liver ribonucleic acid (RNA) . Since this purine 

 base is not known to occur in normal rat liver RNA its presence 

 suggests that methylation of RNA has taken place. Earlier evidence 

 of several kinds has suggested that DMN must be activated meta- 

 bolically before it can damage cells, and diazomethane has been 

 suggested as a possible toxic metabolite. Diazomethane is a power- 

 ful methylating (i.e. alkylating) agent, highly toxic and a known 

 mutagen. It has been shown to methylate guanosine preferentially 

 in the seven position in the test tube. Hence it is suggested that the 

 liver necrosis is caused by methylation of cell constituents, includ- 

 ing RNA and protein, and that the later occurring liver cancer may 

 be related to the presence of RNA containing the abnormal purine 

 base, 7-methyl guanine. 



Chlorpromazine 



The "tranquilizer" chlorpromazine inhibits cytochrome oxi- 

 dase and phosphorylase systems in the rat's brain (Abood, 1955). 

 In liver cells in vitro it interferes highly selectively with one or two 

 of the phosphorylation steps during oxidative phosphorylation 

 (Dawkins, Judah & Rees, 1959) . Chlorpromazine produces no 

 definite structural damage in cells though it leads to jaundice 

 associated with stasis of bile flow within the minute bile passages 

 of the liver. 



