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. 2024 Dec;42(8):e70010.
doi: 10.1002/cbf.70010.

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

Julia Gabrieli Bender  1 , Rafael Teixeira Ribeiro  1 , Ângela Beatris Zemniaçak  1 , Rafael Palavro  1 , Rafael Aguiar Marschner  2 , Simone Magagnin Wajner  2 , Ediandra Tissot Castro  1 , Guilhian Leipnitz  1   3 , Moacir Wajner  1   3   4 , Alexandre Umpierrez Amaral  1   5
Affiliations

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

Julia Gabrieli Bender et al. Cell Biochem Funct. 2024 Dec.

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.

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

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References

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