Oxidation of Reduced Porphyrins by the Mitochondrial Electron Transport Chain: Stimulation by Iron and Potential Role of Reactive Oxygen Species

Abstract

Numerous studies have demonstrated a contributory role of iron in the pathogenesis of various inherited and chemically-induced disorders of porphyrin metabolism (porphyrias) (De Matteis et al, 1988, Smith and Francis, 1987, Lambrecht et al, 1988). However, the precise mechanism by which iron leads to excess tissue porphyrin accumulation and excretion in these disorders remains to be determined. Recent studies from these laboratories (Woods and Calas, 1989) have demonstrated that reduced porphyrins (porphyrinogens) are readily oxidized in vitro by reactive oxidizing species, such as superoxide (O ⁻₂ ) and hydroxyl (OH·) radicals, and that this effect is dramatically stimulated by the presence of iron compounds in the reaction mixture. Inasmuch as mitochondria are a principal locus both of porphyrin metabolism (e.g. Tait, 1978) as well as of the generation of reduced oxygen species (O ⁻₂ ), H₂O₂) (Forman and Boveris, 1982) in cells, it is reasonable to postulate that, in the presence of excess iron, reduced porphyrins could be oxidized by reactive oxidants derived from the mitochondrial electron transport chain, contributing to the accumulation and excretion of oxidized porphyrins observed in iron-exacerbated porphyrinopathies. The present studies were conducted to test the hypothesis that reduced porphyrins are oxidized by reactive oxidants derived from the mitochondrial electron transport chain in the presence of iron.