4-chloro-3-hydroxyanthranilate inhibits brain 3-hydroxyanthranate oxidase |
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| Institution: | 1. Laboratory of Neurophysiology and Section on Analytical Biochemistry, Bethesda, MD 20892 USA;2. Laboratory of Clinical Science, Building 10, Room 3D40 National Institute of Mental Health, Bethesda, MD 20892 USA;1. Laboratory of Liver Regeneration, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Geuman-dong, Duckjin-gu, Jeonju, 561-712, South Korea;2. Department of Biochemistry, School of Medical Sciences, Kathmandu University, Dhulikhel, Kavre, Nepal;3. Department of Surgery, Division of Pediatric Surgery, Stanford University School of Medicine, PSRL, 257 Campus Drive, Stanford, CA 94305-5148, USA;4. Department of Surgery, Chonbuk National University Medical School, 634-18 Geuman-dong, Duckjin-gu, Jeonju, 516-712, South Korea;1. Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA;2. Kyung Hee University, School of Medicine, Seoul, South Korea |
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| Abstract: | Quinolinic acid is synthesized from 3-hydroxyanthranilic acid via 3-hydroxyanthranilic acid oxidase. In liver, 4-chloro-3-hydroxyanthranilic acid inhibits 3-hydroxyanthranilic acid oxidase. To determine whether 4-chloro-3-hydroxyanthranilic acid also inhibits 3-hydroxyanthranilic acid oxidase in brain, 3-hydroxyanthranilic acid was injected into the cisterna magna of rats either with or without 4-chloro-3 hydroxyanthranilic acid. 3-Hydroxyanthranilic acid increased quinolinic acid concentrations throughout the brain. 4-Chloro-3-hydroxyanthranilic acid attenuated increases in brain quinolinic acid. These observations indicate that 4-chloro-3-hydroxyanthranilic acid inhibits 3-hydroxyanthranilic acid oxidase in brain.Quinolinic acid is a well established systemic metabolite of l-tryptophan which has been shown to be present in brain (Wolfensberger et al., 1983; Heyes and Markey, 1988a). QUIN has proved to be a convulsant (Lapin, 1982), neurotoxin (Schwarcz et al., 1983) and agonist of N-methyl-D-aspartate receptors (Perkins and Stone, 1983) when injected directly into the central nervous system of experimental animals. Therefore increased concentrations of QUIN in brain may have neoropathologic consequences. l-Tryptophan is converted to QUIN via the kynurenine pathway. The precursor of QUIN, 2-amino-3-carboxymuconic semialdehyde is synthesized from 3-hydroxyanthranilic acid (3-HAA) by the action of 3-hydroxyanthranilic acid oxidase (3-HAA/OX) in liver and brain (Foster et al., 1986; Okuno et al., 1987). QUIN is then formed from 2-amino-3-carboxymuconic semialdehyde by a spontaneous, non-enzymatic reaction. In liver, 3-HAA/OX is inhibited by 4-chloro-3-hydroxyantranilic acid (CL-HAA; Parli et al., 1980). In the present study, rats were given an intracisternal injection of 3-HAA and the resultant increases in regional brain QUIN concentrations quantified by gas chromatography/mass spectrometry (Heyes and Markey, 1988a,b). To determine whether CL-HAA inhibit 3-hydroxyanthranilic acid oxidase in brain, CL-HAA was co-administered with 3-HAA to see whether increases in QUIN were attenuated. |
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