Alteration of kynurenic acid concentration in rat plasma following optically pure kynurenine administration: a comparative study between enantiomers.
L-Kynurenine (KYN), a tryptophan metabolite, is metabolized to kynurenic acid (KYNA), which is an antagonist of N-methyl-D-aspartate and alpha7 nicotinic acetylcholine receptors, by kynurenine aminotransferase (KAT) I and KAT II. In this study, optically pure KYN, namely L-KYN or D-KYN, was administered intraperitoneally to male Sprague-Dawley rats (16.3 micromol kg(-1)), and the change in plasma KYNA was investigated by using column-switching high-performance liquid chromatography (HPLC) with fluorescence detection. Unexpectedly, no remarkable alteration in the plasma KYNA was observed when a natural isomer, L-KYN, was administered, whereas plasma KYNA concentration was unequivocally increased when an unnatural isomer, D-KYN, was administered. Serum protein bindings of L-KYN and D-KYN were also studied, and the protein binding of L-KYN (approximately 65%) in rat serum was larger than that of D-KYN (approximately 12%), suggesting that D-KYN may be easily incorporated and metabolized in tissues during blood circulation to generate KYNA in mammals. In addition, the increase in plasma KYNA by the administration of D-KYN was suppressed in rats pretreated with a selective inhibitor of D-amino acid oxidase (DAAO), 5-methylpyrazole-3-carboxylic acid (80 mg/kg). These results suggest that DAAO might be responsible for the production of KYNA from D-KYN in vivo.
Fukushima
Takeshi
T
Division of Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Shizuoka, Japan. t-fukushima@phar.toho-u.ac.jp
Sone
Yukiko
Y
Mitsuhashi
Shogo
S
Tomiya
Masayuki
M
Toyo'oka
Toshimasa
T
D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors; D003839:Deoxyadenosines / Q000494:pharmacology; D007736:Kynurenic Acid / Q000097:blood* / Q000378:metabolism; D007737:Kynurenine / Q000008:administration & dosage*; D008297:Male; D008956:Models, Chemical; D011485:Protein Binding; D011720:Pyrazoles / Q000097:blood / Q000494:pharmacology; D011721:Pyrenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013997:Time Factors
D003839:Deoxyadenosines; D011720:Pyrazoles; D011721:Pyrenes; C068173:N-(deoxyadenosin-8-yl)-2-aminopyrene; D007737:Kynurenine; D003605:D-Amino-Acid Oxidase; D007736:Kynurenic Acid; C005210:5-methylpyrazole-3-carboxylic acid