RADIO-PROTECTIVE ACTION' OF 5-HVDROXV IRM' lAM IM. 



Selective Toxicity 

 A review of the subject is beyond the scope of this paper but has been given 

 bv Albert*' **. It is based on the original conception of Ehrlich of a relatively 

 specific metabolite-receptor combination. Today, the receptor is considered 

 a macromolecule (usually an enzyme), and the combination with a metabolite 

 involves : 



{{) the ability of a drug to reach its receptor — a quality at least partly 

 dependent on physico-chemical characteristics (molecular size, lipoid 'water 

 partition coelFicicnts, ionization constant, etc.). Also, active transport 

 mechanisms may be involved requiring expenditure of energy, obtained 

 from the simultaneous oxidation of carbohydrates 



(//) a steric similarity of drug and its analogues, for specific receptor 

 combination 



(///) a chemical bonding usually due to secondary valencies (hydrogen 

 bonds, ionic bonds, multiple van der Waal's bonds) . The bonding is rather 

 readily severed {e.g. by washing in water) 



{iv) competitive antagonism betw^een a metabolite and sterically similar 

 antimetabolite, expressed quantitatively as a 50 per cent inhibitory index of 

 the molar ratio of metabolite and its analogue 



[v) the receptor macromolecule, blocked by a metabolite, can no longer 

 perform one of the metabolic duties within the cell, and pharmacological 

 eflfect occurs. Whilst this constitutes the favoured hypothesis of action 

 postulated by Woolley^** for naturally occurring metabolites, a more complex 

 situation prevails in the case of metabolites and their analogues, which are 

 normally not actively involved in basal metabolism but which cause pharma- 

 cological effects when endogenously released in the organism or exogenously 

 administered {e.g. catechol amines, 5-hydroxytryptamine, and their respective 

 antimetabolites). However a quantitative competitive inhibition prevails in 

 this three-cornered situation of receptor, metabolite and antimetabolite, 

 similar to the more simple relationship already discussed. 



Relationship of Selective Toxicity to Radio-protective Effect of Metabolites in vivo 

 If a metabolite e.g. 5-hydroxytryptamine (serotonin; 5-hydroxy-3-(beta- 

 aminoethyl) indole) is capable of entering the zone of influence in a cell, 

 where vital macromolecules are vulnerable to ionizing radiations, and affords 

 protection at this site, this protective action based on the physico-chemical 

 hypothesis of competition for free radicals, should not l)e diminished by the 

 presence of a specific analogue (antimetabolite) at this site. 



On the other hand, if the inactivation of oxidizing radicals is determined 

 by an alteration in basal metabolism due to a metabolite-receptor com- 

 bination, which interferes with the normal metabolic cycle. Redox potentials, 

 intracellular oxygen tension, etc., antimetabolites would be expected to 

 modify (reduce) this specific radio-protective effect selectively in those cells 

 which possess specific receptors. This condition should liold /// vivo and 

 in vitro for a particular tissue. 



As a third alternative, generalized radio-protection as a result of anoxaemia, 

 \\'\\\ result from selective toxicity, where the receptors are present in smooth 

 muscle, but the radio-protective action of the metabolite for a non-muscular 

 tissue in vivo, should be reduced when exposed in vitro under suitable conditions. 



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