Investigations on the role of free radical processes in hexachlorobenzene-induced porphyria in mice.
Male C57Bl/10 mice were chronically fed hexachlorobenzene (HCB) (0.02% of the diet) alone or in combination with a single subcutaneous dose of iron (12.5 mg iron per mouse). After eight weeks the group of mice pretreated with the iron overload was highly sensitized to the porphyrogenic effect of HCB, as shown by liver porphyrin accumulation. A synergistic effect of iron was evident on other parameters too, such as HCB-induced hepatic damage, activation of type O of xanthine oxidase, and decreased activity of copper zinc superoxide dismutase and glutathione peroxidase(s). None of these parameters was affected by iron alone. Iron alone and in association with HCB markedly raised the level of lipid peroxides, the increase in the HCB group being smaller. The combined treatment resulted in a significant reduction of HCB's inductive effects on microsomal heme and cytochromes P-450 and b5 and on the activity of aryl hydrocarbon hydroxylase. The content of nonprotein sulfhydryl groups was reduced to the same extent in mice treated with HCB or HCB plus iron. The results suggest that reactive intermediates such as are formed by lipid peroxidation are not sufficient on their own to create the conditions for uroporphyrinogen decarboxylase impairment, as evident in the group of mice receiving iron overload alone. Conversely, HCB administration induced a specific condition of imbalance in the liver between formation and inactivation of reactive intermediates which was associated with hepatic porphyrin accumulation and was potentiated by concomitant administration of iron.
Rizzardini
M
M
Unit for Heme and Hemoproteins Metabolism, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Graziani
A
A
Carugo
C
C
Cantoni
L
L
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D002722:Chlorobenzenes / Q000633:toxicity*; D005609:Free Radicals; D006581:Hexachlorobenzene / Q000633:toxicity*; D007501:Iron / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011164:Porphyrias / Q000139:chemically induced*; D011166:Porphyrins / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D002722:Chlorobenzenes; D005609:Free Radicals; D008054:Lipid Peroxides; D011166:Porphyrins; D006581:Hexachlorobenzene; D007501:Iron; D014969:Xanthine Oxidase