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      Tryptophan Metabolism via the Kynurenine Pathway in Experimental Chronic Renal Failure

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          Background: Kidneys are involved in tryptophan (TRP) metabolism in two ways. They eliminate TRP derivatives on the one hand, and they produce several enzymes taking part in TRP metabolism mainly via the kynurenine pathway on the other. The aim of the present study was to examine the time-course of changes in the peripheral kynurenine products degradation during experimental chronic renal failure in rats. Methods: Tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid, xanthurenic acid, anthranilic acid and quinolinic acid were determined in plasma using high-performance liquid chromatography technique with UV, fluorescence and electrochemical detection. Results: A decreased TRP level and significant increase in kynurenine pathway metabolite concentrations in plasma of uremic rats were found. Conclusions: Substantial disturbances in the peripheral kynurenic pathway were observed in experimental chronic renal failure. They may contribute to several symptoms of uremia.

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          Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine.

          3-Hydroxykynurenine (3-HK) is a tryptophan metabolite whose level in the brain is markedly elevated under several pathological conditions, including Huntington disease and human immunodeficiency virus infection. Here we demonstrate that micromolar concentrations (1-100 microM) of 3-HK cause cell death in primary neuronal cultures prepared from rat striatum. The neurotoxicity of 3-HK was blocked by catalase and desferrioxamine but not by superoxide dismutase, indicating that the generation of hydrogen peroxide and hydroxyl radical is involved in the toxicity. Measurement of peroxide levels revealed that 3-HK caused intracellular accumulation of peroxide, which was largely attenuated by application of catalase. The peroxide accumulation and cell death caused by 1-10 microM 3-HK were also blocked by pretreatment with allopurinol or oxypurinol, suggesting that endogenous xanthine oxidase activity is involved in exacerbation of 3-HK neurotoxicity. Furthermore, NADPH diaphorase-containing neurons were spared from toxicity of these concentrations of 3-HK, a finding reminiscent of the pathological characteristics of several neurodegenerative disorders such as Huntington disease. These results suggest that 3-HK at pathologically relevant concentrations renders neuronal cells subject to oxidative stress leading to cell death, and therefore that this endogenous compound should be regarded as an important factor in pathogenesis of neurodegenerative disorders.
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            Cloning and Functional Expression of a Soluble Form of Kynurenine/α -Aminoadipate Aminotransferase from Rat Kidney

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              2-Oxoacids Regulate Kynurenic Acid Production in the Rat Brain


                Author and article information

                S. Karger AG
                March 2002
                25 February 2002
                : 90
                : 3
                : 328-335
                Departments of aPharmacodynamics, and bII General Surgery, Medical Academy of Bialystok, Poland
                49069 Nephron 2002;90:328–335
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 2, References: 31, Pages: 8
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/49069
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