Stimulation of porphyrinogen oxidation by mercuric ion. II. Promotion of oxidation from the interaction of mercuric ion, glutathione, and mitochondria-generated hydrogen peroxide.
Previous studies have shown that mercuric ion (Hg2+) reacts with GSH and H2O2 in vitro to form reactive species capable of oxidizing reduced porphyrins (porphyrinogens). This effect is independent of the presence of iron in the reaction mixture. The present studies demonstrate that Hg2+ and GSH can interact in biologically relevant concentrations with H2O2 generated by the mitochondrial electron transport chain to promote oxidation of porphyrinogens via comparable mechanisms. Mitochondria from rat liver or kidney readily oxidize uroporphyrinogen when H2O2 production is stimulated by the presence of a respiratory chain substrate (NADH, succinate) and an electron transport inhibitor (e.g., NaN3). Porphyrinogen oxidation by mitochondria is significantly increased by the addition of Hg2+ and GSH, in a molar ratio of approximately 3:5, to the reaction mixture. Stimulation of porphyrinogen oxidation in the presence of Hg2+ plus GSH increases proportionately with the concentration of mitochondrial protein in the reaction cuvettes but decreases with diminished H2O2 production by the electron transport chain. Studies with reactive oxidant scavengers suggest the participation of reactive oxygen species in Hg plus GSH stimulation of mitochondrial porphyrinogen oxidation. These findings support the hypothesis that Hg2+ and GSH interact with mitochondria-generated H2O2 to promote propagation of reactive oxidants or other free radical species, which, in turn, oxidize reduced porphyrins proximal to mitochondrial membranes. These results suggest a mechanistic explanation for the porphyrinogenic action of mercury compounds, as well as for the oxidative damage to target cell constituents associated with mercury exposure.
Woods
J S
JS
Department of Environmental Health, University of Washington, Seattle 98195.
Calas
C A
CA
Aicher
L D
LD
D000818:Animals; D004579:Electron Transport; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008627:Mercuric Chloride / Q000494:pharmacology* / Q000633:toxicity; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011165:Porphyrinogens / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D005609:Free Radicals; D011165:Porphyrinogens; D008627:Mercuric Chloride; D006861:Hydrogen Peroxide; D005978:Glutathione