title: Kynurenic acid and 3-hydroxykynurenine production from D-kynurenine in mice.
abstract: Kynurenic acid (KYNA), an antagonist of the α7 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.
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Wang
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Notarangelo
authors.forename: Ji-Zuo
authors.initials: JZ
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000502:physiology; D002384:Catalysis; D005260:Female; D007736:Kynurenic Acid / Q000097:blood / Q000138:chemical synthesis / Q000378:metabolism*; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013237:Stereoisomerism; D014364:Tryptophan / Q000008:administration & dosage
chemical_list: C005045:3-hydroxykynurenine; D007737:Kynurenine; D014364:Tryptophan; D007736:Kynurenic Acid