Damage to rat liver mitochondria promoted by delta-aminolevulinic acid-generated reactive oxygen species: connections with acute intermittent porphyria and lead-poisoning

Abstract

delta-Aminolevulinic acid is a heme precursor accumulated in acute intermittent porphyria and lead-poisoning, which supposedly triggers the typical clinical expression associated with these diseases. Considering that: (i) erythrocyte anti-oxidant enzymes are abnormally high in patients with both disorders and (ii) delta-aminolevulinic acid autoxidation generates reactive oxygen species, a possible contribution of reactive oxygen species in the pathophysiology of these disorders is explored here. Evidence is provided that delta-aminolevulinic acid (2-15 mM) induces damage to isolated rat liver mitochondria. Addition of delta-aminolevulinic acid disrupts the mitochondrial membrane potential, promotes Ca2+ release from the intramitochondrial matrix and releases the state-4 respiration, thus enhancing the permeability of the membrane to H+. The lesion was abolished by catalase, superoxide dismutase (both enzymes inhibit delta-aminolevulinic acid autoxidation) and ortho-phenanthroline, but not by mannitol; added H2O2 induces damage poorly. These results suggest the involvement of deleterious reactive oxygen species formed at particular mitochondrial sites from transition metal ions and delta-aminolevulinic acid-generated peroxide and/or superoxide species. These observations might be compatible with previous work showing hepatic mitochondrial damage in liver biopsy samples of acute intermittent porphyria patients.