The liver in uroporphyria : a biochemical and morphological study

The aim of the work described in this thesis was to examine further the mechanisms involved in the accumulation of uroporphyrins in the liver, i.e., the role of iron and an increased activity of one of the preceding enzymes in the heme biosynthetic pathway, PBG-D, in the porphyrinogenic process in experimental uroporphyria and in PCT. In the previous paragraphs, the proposed role of iron in the development of uroporphyria has been discussed. However, a study on the time-sequence relationship between iron accumulation and uroporphyrin production in the liver has not been performed. In addition, the nature of the iron pool involved in this process has not been established. The role of iron in uroporphyria has been explained by its ability to participate in peroxidative and free radical reactions. Desferrioxamine, an iron chelator, has been described to diminish uroporphyrin accumulation in the liver. At present, the specific effects of desferrioxamine on iron accumulation, free radical-mediated reactions, uroporphyrin accumulation and URO-D activity in the liver have not been studied in experimental uroporphyria. It has been reported that the activity of the enzyme PBG-D is increased in erythrocytes and livers of patients with PCT. It is not clear whether this increased PBG-D activity can be observed both in animals with experimental uroporphyria and in humans with sporadic and familial forms of PCT. An increased PBG-D activity could explain the absence of acute attacks in PCT. Moreover, an increased PBG-D activity could also provide an additional explanation for uroporphyrin accumulation in experimental and human uroporphyria.