Enzymes 61 



systems. Such injuries may be of endogenous origin or may de due 

 to exogenous toxins, to deficiency states or to enzymic dysfunction 

 of genetic origin. 



ENDOGENOUS INJURY: KERNICTERUS 

 (NUCLEAR JAUNDICE) 



Kernicterus is a disease of the newborn in which there is bili- 

 rubinaemia and jaundice together with degeneration and bile- 

 staining of parts of the brain, especially the nuclei of the basal 

 ganglia. The condition is an interesting example of injury due to 

 a temporary lack of enzymes controlling the detoxication of a 

 potentially dangerous metabolite, namely indirect-reacting bili- 

 rubin (Billing and Lathe, 1958) . When tested on isolated mito- 

 chondria, this substance brings oxidative phosphorylation to a 

 standstill and in higher concentrations stops the oxidation of tri- 

 carboxylic acid cycle substrates. 



Indirect-reacting bilirubin is formed from the haem liberated 

 by the breakdown of red blood cells and is normally converted in 

 the liver to the non-toxic direct-reacting (i.e. water soluble) pig- 

 ment. This detoxication is accomplished enzymatically by conjuga- 

 tion with glucuronic acid in the presence of a coenzyme, uridine 

 triphosphate (UTP) . The process also requires ATP (Fig. 7) . The 

 newborn and especially the premature liver performs this enzyma- 

 tic reaction inadequately thus accounting for the enhanced toxicity 

 in the neonate of the many compounds normally detoxicated by 

 this pathway. If the level of indirect-reacting bilirubin is especially 

 high, due for example to massive haemolysis in blood group incom- 

 patibility such as Rh disease, large amounts of toxic pigment 

 accumulate and damage particularly sensitive tissues, i.e. brain cells. 

 The level of conjugating and detoxicating enzymes is very low in the 

 newborn liver but rises steeply in the first few days of life. 



Large doses of vitamin K are known to precipitate kernicterus 

 in premature babies. This is thought to be due to interference with 

 the supply of reduced glutathione, a coenzyme necessary for glycoly- 

 sis in red cells and for the formation of haemoglobin from methae- 

 moglobin. In the absence of reduced glutathione there is excessive 

 haemolysis and a subsequent rise in circulating indirect-reacting 



