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.