1. Oxidative Stress Associated With Increased Reactive Nitrogen Species Generation in the Liver and Kidney Caused by a Major Metabolite Accumulating in Tyrosinemia Type 1.
- Author
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Bender JG, Ribeiro RT, Zemniaçak ÂB, Palavro R, Marschner RA, Wajner SM, Castro ET, Leipnitz G, Wajner M, and Amaral AU
- Subjects
- Humans, Animals, Rats, HEK293 Cells, Male, Hep G2 Cells, Rats, Wistar, Heptanoates metabolism, Heptanoates pharmacology, Glutathione metabolism, Tyrosinemias metabolism, Tyrosinemias pathology, Liver metabolism, Oxidative Stress drug effects, Kidney metabolism, Kidney pathology, Reactive Nitrogen Species metabolism
- Abstract
Tyrosinemia type 1 (TT1) is caused by fumarylacetoacetate hydrolase activity deficiency, resulting in tissue accumulation of upstream metabolites, including succinylacetone (SA), the pathognomonic compound of this disease. Since the pathogenesis of liver and kidney damage observed in the TT1-affected patients is practically unknown, this study assessed the effects of SA on important biomarkers of redox homeostasis in the liver and kidney of adolescent rats, as well as in hepatic (HepG2) and renal (HEK-293) cultured cells. SA significantly increased nitrate and nitrite levels and decreased the concentrations of reduced glutathione (GSH) in the liver and kidney, indicating induction of reactive nitrogen species (RNS) generation and disruption of antioxidant defenses. Additionally, SA decreased the GSH levels and the activities of glutathione peroxidase, glutathione S-transferase, glutathione reductase, and superoxide dismutase in hepatic and renal cells. Noteworthy, melatonin prevented the SA-induced increase of nitrate and nitrite levels in the liver. Therefore, SA-induced increase of RNS generation and impairment of enzymatic and nonenzymatic antioxidant defenses may contribute to hepatopathy and renal disease in TT1., (© 2024 John Wiley & Sons Ltd.)
- Published
- 2024
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