Inhibitory effects of kynurenic acid, a tryptophan metabolite, and its derivatives on cytosolic sulfotransferases.
KYNA (kynurenic acid) is an endogenous metabolite of tryptophan in the kynurenine pathway and has been characterized as an antagonist of ionotropic glutamate receptors. In addition, we have reported this endogenous compound as a potent inhibitor of SULTs (cytosolic sulfotransferases). In the present study we characterized the inhibitory effects of KYNA on several human (h) and mouse (m) recombinant SULTs. No sulfate metabolite of KYNA was detected with mouse and human SULTs examined under the conditions used, suggesting that it is a bona fide inhibitor of SULTs. Among the mouse enzymes examined, KYNA exhibited selective inhibitory effects on Sult1b1-mediated sulfation of various compounds with IC50 values in the low micromolar range (2.9-4.9 microM). KYNA also exerted an inhibitory activity towards hSULT1A1 and hSULT1B1. The inhibitory potency of KYNA for mSult1b1 was stronger than that of 2,6-dichloro-4-nitrophenol, a known non-specific SULT inhibitor, whereas the potencies of these two inhibitors for hSULT1B1 were comparable. The inhibitory characteristics of KYNA were clearly distinct from those of mefenamic acid, a selective inhibitor of SULT1A enzymes. The KYNA derivatives 5,7-dichlorokynurenic acid and L689,560 exhibited preferential inhibitory effects on hSULT1A1 and hSULT1B1 respectively. Interestingly, gavestinel, another KYNA derivative, was found to be an extremely potent inhibitor of hSULT1B1. Finally, we have demonstrated that the mechanism underlying the KYNA inhibition varied depending on the enzyme and substrate involved. Taken together, the present results unveil another distinct aspect of KYNA and its derivatives as an inhibitor of SULTs.
Senggunprai
Laddawan
L
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
Yoshinari
Kouichi
K
Yamazoe
Yasushi
Y
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007736:Kynurenic Acid / Q000494:pharmacology*; D008528:Mefenamic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009596:Nitrophenols / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D009596:Nitrophenols; D011994:Recombinant Proteins; D008528:Mefenamic Acid; C015802:2,6-dichloro-4-nitrophenol; D014364:Tryptophan; D015238:Sulfotransferases; D007736:Kynurenic Acid