Porphyrin metabolism in congenital erythropoietic porphyria

Abstract

Meso-hydroxyuroporphyrin I, B-hydroxypropionic acid uroporphyrin I, hydroxyacetic acid uroporphyrin I and peroxyacetic acid uroporphyrin I have been isolated from the urine and plasma of patients with congenital erythropoietic porphyria (CEP) by high-performance liquid chromatography and characterized by liquid secondary ion mass spectrometry and chemical properties. The physico-chemical properties of these compounds have been studied. The hydroxy- and peroxyacetic acid- uroporphyrin I derivatives are the true metabolites of uroporphyrinogen I in vivo and their presence in urine and plasma is a common feature of CEP. The absence of these derivatives in duodenal aspirate and faeces suggests that they are of erythropoietic origin. The mechanism of formation of the hydroxy- and peroxyacetic acid- uroporphyrin I has been investigated. Peroxyacetic acid uroporphyrin I is formed from uroporphyrinogen I in the presence of H202 and iron while the hydroxylated uroporphyrin I derivatives are most probably produced by hydroxyl radicals generated during the formation of peroxyacetic acid uroporphyrin I. Destruction of porphyrins is found in the same reaction and can be prevented bydesferrioxamine, indicating that it is due to hydroxyl radicals. The formation of peroxyacetic acid- and hydroxyuroporphyrin I derivatives are uroporphyrinogen I concentration dependent. These derivatives can only be formed when uroporphyrinogen I is accumulated to a certain concentration (approx. 1-2 ~M) and the formation is then proportional to the uroporphyrinogen I concentration. The peroxylation reaction has been shown to take place only at the acetic acid side-chains of porphyrinogen and not at the propionic acid side-chains. The peroxylation reaction can therefore take place whenever a porphyrinogen with an acetic acid substituent is accumulated. Oral charcoal therapy failed to reduce the porphyrins accumulated in vivo in a patient with CEP. Uroporphyrin I, the major porphyrin accumulating in CEP, was not excreted into bile and interruption of the enterohepatic circulation by binding porphyrins onto charcoal therefore does not benefit CEP. It may, however, be effective in the treatment of hepatic porphyrias in which the accumulated porphyrins are mainly excreted via the gut lumen.