• Lead poisoning = porphyria (disease of erythroid or hepatic origins that causes defects in specific enzymes in heme biosynthetic pathway)
  • Superoxide dimutase (SOD – helps breakdown potentially harmful oxygen molecules) and glutathione peroxidase (GSH – catalyzes breakdown of HO → H2O + O2) reported to increase in patients w lead poisoning
    • SODs can be induced by oxygen exposure
    • Increased SOD activity in lungs is associated with tolerance to hyperoxia
    • significant increase in SOD activities in workers occupationally exposed to lead (88% above 25µg Pb/100g blood)
      • SOD levels at lead concentrations above 40µg Pb/100g blood coincidental to lead threshold for ALA urinary excretion
  • Heme precursor (d-aminolevulinic acid) accumulated in both diseases
  • Lead inhibits ALAD (ALA dehydratase)
    • ALA autooxidzes and promotes hemoglobin oxidation with production of free radical species
  • Superoxide free radical (O-2), hydrogen peroxide (H2O2), hydroxyl radical (*OH), and singlet oxygen (1O2)
    • Deleterious effects on body tissues
    • Can oxidize membrane fatty acids → lipid peroxidation, modify proteins, damage DNA
    • 1O2 is most important reactive oxygen species in photo oxidative cell damage
      • Lipid perodidation, amino acid oxidation, cross linking of proteins in cell membranes
  • In heme synthesis:
    • Lead is a potent inhibitor of ALA dehydratase
      • ALA synthase in heme synthesis
    • Lead inhibits insertion of ferrous iron into protoporphyrin ring by ferrochelatase
    • Leads to porphyrias accumulation 
      • Leads to skin damage
      • Photosensitization in animals
      • Photosensitizing reactions in porphyria require oxygen
      • Type 1:
        • Photochemically initiated autooxidation
      • Type 2:
        • Oxygen becomes electronically excited by interaction with suitable triplet species
  • ALA accumulation…
    • ALA derived neurotoxicity may be due to free radicals produced during ALA autoxidation
  • Superoxide generation during ALA autoxidation is evidenced by parallel reduction of ferricytochrome C
    • Confirmed via ESR spin-trapping experiments

We would make our own reaction scheme for this (the pictures here are copied) (This page would connect to the impacts of ALAD inhibition, so that page can focus more on the mechanism than deleterious impacts of free radicals)