58 The Chemistry of the Injured Cell 



a consequent rise in basal metabolic rate. Observation of this 

 property without realisation of its significance led to a disastrous 

 utilisation of 2:4 dinitrophenol as a "slimming" compound. 



Fluoroacetate 



Another classical instance of a respiratory poison acting at a 

 specific site is fluoroacetate, a substance which may cause death in 

 convulsions within a few hours. Fluoroacetate acts by preventing 

 the oxidation of citrate to a ketoglutarate (Fig. 6) . It does so by 

 inhibiting the enzyme aconitase which is required for this reaction. 

 Before it can exert this effect, fluoroacetate is first "activated" by 

 the body to form fluoracetyl CoA. This substance then condenses 

 with oxaloacetate and is further metabolised to fluorocitrate which 

 then inhibits competitively the oxidation of citrate. As a result the 

 respiratory cycle and its attendant energy yielding reactions are 

 brought to a standstill. The conversion of harmless fluoracetate to 

 poisonous fluorocitrate was termed by Peters "lethal synthesis." 



Carbon Monoxide 



Carbon monoxide gas interrupts respiration in a different 

 fashion by combining with haemoglobin and thus preventing this 

 substance from acting as an oxygen carrier. The gas has another 

 property, that of complexing with cytochrome oxidase (Fig. 3) and 

 this may possibly account for some of the later manifestations of 

 non-fatal carbon monoxide poisoning. 



Lewisite, Mustard Gas and the Nitrogen Mustards 



These compounds were first studied as chemical warfare agents, 

 one of whose effects was to cause blistering and necrosis, especially 

 of skin. The chief chemical property, which is believed to underlie 

 their toxic action, is an affinity for -SH groups. Thus lewisite reacts 

 with glutathione and thereby inactivates this vital substance. 

 Lewisite is also a powerful inhibitor of pyruvic oxidase, the enzyme 

 system catalysing the oxidation of pyruvate (Fig. 6) . The toxic 

 effects of lewisite on the animal, and the inhibition of pyruvic 

 oxidase could both be prevented by di-thiol antidotes such as 

 dimercaptopropanol (BAL) , but not by monothiols (i.e. com- 



