Mechanism of increases in L-kynurenine and quinolinic acid in renal insufficiency.
Marked increases in metabolites of the L-tryptophan-kynurenine pathway, L-kynurenine and quinolinic acid (Quin), were observed in serum and cerebrospinal fluid (CSF) of both the rat and human with renal insufficiency. The mechanisms responsible for their accumulation after renal insufficiency were investigated. In patients with chronic renal insufficiency, elevated levels of serum L-kynurenine and Quin were reduced by hemodialysis. In renal-insufficient rats, Quin and L-kynurenine levels in serum, brain, and CSF were also increased parallel to the severity of renal insufficiency. Urinary excretion of Quin (3.5-fold) and L-kynurenine (2.8-fold) was also increased. Liver L-tryptophan 2,3-dioxygenase activity (TDO), a rate-limiting enzyme of the kynurenine pathway, was increased in proportion to blood urea nitrogen and creatinine levels. Kynurenine 3-hydroxylase and quinolinic acid phosphoribosyltransferase were unchanged, but the activities of kynureninase, 3-hydroxyanthranilate dioxygenase, and aminocarboxymuconate-semialdehyde decarboxylase (ACMSDase) were significantly decreased. Systemic administrations of pyrazinamide (ACMSDase inhibitor) increased serum Quin concentrations in control rats, demonstrating that changes in body ACMSDase activities in response to renal insufficiency are important factors for the determination of serum Quin concentrations. We hypothesize the following ideas: that increased serum L-kynurenine concentrations are mainly due to the increased TDO and decreased kynureninase activities in the liver and increased serum Quin concentrations are due to the decreased ACMSDase activities in the body after renal insufficiency. The accumulation of CSF L-kynurenine is caused by the entry of increased serum L-kynurenine, and the accumulation of CSF Quin is secondary to Quin from plasma and/or Quin precursor into the brain.
Saito
K
K
Department of Laboratory Medicine, Gifu University School of Medicine, Gifu 500-8705, Japan. saito@cc.gifu-u.ac.jp
Fujigaki
S
S
Heyes
M P
MP
Shibata
K
K
Takemura
M
M
Fujii
H
H
Wada
H
H
Noma
A
A
Seishima
M
M
D000328:Adult; D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D007737:Kynurenine / Q000097:blood* / Q000134:cerebrospinal fluid; D050601:Kynurenine 3-Monooxygenase; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010430:Pentosyltransferases / Q000378:metabolism; D011718:Pyrazinamide / Q000378:metabolism; D017378:Quinolinic Acid / Q000097:blood* / Q000134:cerebrospinal fluid; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000378:metabolism; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating)
D004791:Enzyme Inhibitors; D011718:Pyrazinamide; D007737:Kynurenine; D014364:Tryptophan; D006899:Mixed Function Oxygenases; D014366:Tryptophan Oxygenase; C023440:anthranilate 2,3-dioxygenase(deaminating); D050601:Kynurenine 3-Monooxygenase; D010430:Pentosyltransferases; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating); D006867:Hydrolases; C021480:kynureninase; D002262:Carboxy-Lyases; C024396:aminocarboxymuconate-semialdehyde decarboxylase; D017378:Quinolinic Acid