Hepatic damage and oxidative stress induced by Griseofulvin in mice.
Erythropoietic Protoporphyria (EPP) is a disease associated with ferrochelatase deficiency, which produces accumulation of protoporphyrin IX (PROTO IX) in erythrocytes, liver and skin. In some cases, a severe hepatic failure and cholestasis was observed. Griseofulvin (Gris) develops an experimental EPP with hepatic manifestations in animals. The aim of this work was to further characterize this model studying its effect on different metabolisms in mice Gris feeding (0-2.5%, 7 and 14 days). PROTO IX accumulation in liver, blood and feces, induction of ALA-S activity, and a low rate of Holo/Apo tryptophan pyrrolase activity was produced, indicating a reduction of free heme pool. The progressive liver injury was reflected by the aspect and the enlargement of liver and the induction of hepatic damage. Liver redox balance was altered due to porphyrin high concentrations; as a consequence, the antioxidant defense system was disrupted. Heme oxygenase was also induced, however, at higher concentrations of antifungal, the free heme pool would be so depleted that this enzyme would not be necessary. In conclusion, our model of Protoporphyria produced liver alterations similar to those found in EPP patients.
Martinez
M Del C
Mdel C
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), Hospital de Clínicas José de San Martín, University of Buenos Aires, Argentina. mcmartin@qb.fcen.uba.ar
Afonso
S G
SG
Meiss
R P
RP
Buzaleh
A M
AM
Batlle
A
A
D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004195:Disease Models, Animal; D006118:Griseofulvin / Q000633:toxicity*; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D046351:Protoporphyria, Erythropoietic / Q000139:chemically induced; D011524:Protoporphyrins / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000378:metabolism
D000935:Antifungal Agents; D011524:Protoporphyrins; D006118:Griseofulvin; D006418:Heme; C028025:protoporphyrin IX; D014366:Tryptophan Oxygenase; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A; D006419:Heme Oxygenase (Decyclizing)