Role of iron in the hydrogen peroxide-dependent oxidation of hexahydroporphyrins (porphyrinogens): a possible mechanism for the exacerbation by iron of hepatic uroporphyria

Abstract

The hypothesis that the accumulation of uroporphyrin, characteristic of uroporphyria, arises at least in part from oxidation of uroporphyrinogen and the molecular basis for the potentiation of the disorder by iron have been investigated. The iron chelates of ethylenediaminetetraacetic acid (EDTA) and nitrilotriacetic acid were very active at promoting the hydrogen peroxide-dependent oxidation of porphyrinogens, and a similar role of iron was found for the NADPH-dependent oxidation of porphyrinogens by liver microsomes in vitro. In contrast, neither the iron chelate of desferrioxamine (DES) nor ferritin iron possessed prooxidant activity, but the latter could be mobilized in an active form by incubation with EDTA. Iron was also found to promote further modification of the porphyrin pigment, leading to marked loss of its Soret absorbance. This latter effect, which could also be inhibited by DES, suggested further oxidative conversion of the accumulating uroporphyrin, but further work is necessary to establish the relevance of this (or similar) reaction to the inhibitor of uroporphyrinogen decarboxylase which has recently been reported. These results suggest a possible mechanism for the exacerbation of uroporphyria by excess iron and also for its marked improvement when the iron stores are diminished, for example, by DES treatment.