Haem oxygenase deficiency

For the effects of haem oxygenase deficiency to be so profound we may well wonder whether some degree of oxidative stress is in fact the norm. If so, then haem oxygenase levels presumably change continuously as part of a flexible and self-regulating feedback mechanism. We shall see in Chapter IS that a continuously high haem oxygenase activity probably does have beneficial effects on our health in old age. 

Zinc protoporphyrin IX is a normal metabolite that is formed in trace amounts during haem biosynthesis. However, in iron deficiency or in impaired iron utilization, zinc becomes an alternative substrate for ferrochelatase and elevated levels of zinc protoporphyrin IX, which has a known low affinity for oxygen, are formed. This zinc-for-iron substitution is one of the first biochemical responses to iron depletion, and erythrocyte zinc protoporphyrin is therefore a very sensitive index of bone-marrow iron status (Labbe et ah, 1999). In addition, zinc protoporphyrin may regulate haem catabolism by acting as a competitive inhibitor of haem oxygenase, the key enzyme of the haem degradation pathway. However, it has been reported... 

The catabolism of haemoglobin yields haem, which is subsequently converted to bilirubin in a two-step process that takes place in the hepatocyte. First, the microsomal enzyme haem oxygenase cleaves the porphyrin ring of haem, generating biliverdin in an energy-utilising reaction. Following this, biliverdin is converted to bilirubin by the cytosolic enzyme biliverdin reductase. As the liver is the active site for biosynthesis of porphyrin and haem, deficiencies in some enzymes of the porphyrin pathway may lead to insufficient haem production and an increase in porphyrin levels, which causes acute porphyria attacks. 

Tsui and co-workers have carried out similar research, and found that TNF-a induced apoptosis of liver cells also occurs when mice are sensitised with D-galactosamine. " The survival of these mice to this treatment can be significantly improved by the administration of CO. The work also shows that HO-1 deficiency increases sensitivity to liver damage. This work is in agreement with the research of Nakao and co-workers, and shows a key link between haem oxygenase and CO in cytoprotective action. 

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