Oxidative Stress Associated With Increased Reactive Nitrogen Species Generation in the Liver and Kidney Caused by a Major Metabolite Accumulating in Tyrosinemia Type 1.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 8305874 Publication Model: Print Cited Medium: Internet ISSN: 1099-0844 (Electronic) Linking ISSN: 02636484 NLM ISO Abbreviation: Cell Biochem Funct Subsets: MEDLINE

Publication: Oxford, England : Wiley-Blackwell
Original Publication: Guildford, Surrey : Butterworth Scientific Ltd., c1983-

Tyrosinemias*/metabolism ; Tyrosinemias*/pathology ; Liver*/metabolism ; Oxidative Stress*/drug effects ; Kidney*/metabolism ; Kidney*/pathology ; Reactive Nitrogen Species*/metabolism; Humans ; Animals ; Rats ; HEK293 Cells ; Male ; Hep G2 Cells ; Rats, Wistar ; Heptanoates/metabolism ; Heptanoates/pharmacology ; Glutathione/metabolism

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.)

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This research was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 402440/2021-8), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, 19/2551-0001662-0), Instituto Nacional de Ciência e Tecnologia - Excitotoxicidade e Neuroproteção (INCT-EN, 465671/2014-4) and Instituto Nacional de Ciência e Tecnologia - Saúde Cerebral (INCT-SC, 406020/2022-1).

Keywords: antioxidant defenses; reactive nitrogen species; redox homeostasis; succinylacetone; tyrosinemia type 1

0 (Reactive Nitrogen Species)
51568-18-4 (succinylacetone)
0 (Heptanoates)
GAN16C9B8O (Glutathione)

Date Created: 20241028 Date Completed: 20241028 Latest Revision: 20241028

20241028

10.1002/cbf.70010

39462834