Kynurenic acid and 3-hydroxykynurenine production from d-kynurenine in mice

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• 作者：Xiao-Dan Wang^a ; ^b ; Francesca M. Notarangelo^a ; Ji-Zuo Wang^b ; Robert Schwarcz^a ; ^{rschwarc@mprc.umaryland.edu}
• 关键词：d-AAO ; d-aminoacid oxidase ; d-3-HK ; d-3-hydroxykynurenine ; d-KYN ; d-kynurenine ; d ; l-3HK ; d ; l-3-hydroxykynurenine ; HPLC ; high performance liquid chromatography ; KAT ; kynurenine aminotransferase(s) ; KYNA ; kynurenic acid ; KMO ; kynurenine 3-monooxygenase ; l-K
• 刊名：Brain Research
• 出版年：2012
• 期刊代码：8_00068993
• 类别：neu
• 出版时间：21 May, 2012
• 卷：1455
• 期：Complete
• 页码：1-9
• 文件大小：576 K

摘要

Kynurenic acid (KYNA), an antagonist of the 伪7 nicotinic acetylcholine receptor and the N-methyl-d-aspartate receptor, and 3-hydroxykynurenine (3-HK), a generator of reactive oxygen species, are neuroactive metabolites of the kynurenine pathway of tryptophan degradation. In the mammalian brain as elsewhere, both compounds derive from a common bioprecursor, l-kynurenine (l-KYN). Recent studies in rats demonstrated that d-kynurenine (d-KYN), a metabolite of the bacterial amino acid d-tryptophan, can also function as a bioprecursor of brain KYNA. We now investigated the conversion of systemically administered d-KYN to KYNA in mice and also explored the possible production of 3-HK in the same animals. Thirty min after an injection of d-KYN or l-KYN (30 mg/kg, i.p.), newly produced KYNA and 3-HK were recovered from plasma, liver, forebrain and cerebellum in all cases. Using a new chiral separation method, 3-HK produced from d-KYN was positively identified as D-3-HK. l-KYN was the more effective precursor of KYNA in all tissues and also exceeded d-KYN as a precursor of brain 3-HK. In contrast, d-KYN was more potent as a precursor of 3-HK in the liver. The production of both KYNA and 3-HK from d-KYN was rapid in all tissues, peaking at 15-30 min following a systemic injection of d-KYN. These results show that biosynthetic routes other than those classically ascribed to l-KYN can account for the synthesis of both KYNA and 3-HK in vivo. This new insight may be of significant physiological or pathological relevance.