Damage to rat liver mitochondria promoted by delta-aminolevulinic acid-generated reactive oxygen species: connections with acute intermittent porphyria and lead-poisoning.
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.
Hermes-Lima
M
M
Departamento de Bioquímica, Universidade de São Paulo, Brazil.
Valle
V G
VG
Vercesi
A E
AE
Bechara
E J
EJ
D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D007855:Lead Poisoning / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D011164:Porphyrias / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000378:metabolism
D000622:Aminolevulinic Acid; D013482:Superoxide Dismutase; D010100:Oxygen; D002118:Calcium