title: Substrate product ratios of enzymes in the kynurenine pathway measured in plasma as indicators of functional vitamin B-6 status.
abstract: BACKGROUND
  Tryptophan metabolism through the kynurenine pathway includes 2 vitamin B-6 [pyridoxal 5'-phosphate (PLP)]-dependent enzymes. We recently showed that plasma 3-hydroxykynurenine (HK) was elevated at low PLP concentrations.
  
  
  OBJECTIVE
  We further evaluated and characterized kynurenine-based indexes as possible markers of functional B-vitamin status in plasma.
  
  
  METHODS
  Cross-sectional and longitudinal data were derived from the Western Norway B-vitamin Intervention Trial, including PLP, kynurenine, HK, kynurenic acid (KA), anthranilic acid, xanthurenic acid (XA), and 3-hydroxyanthranilic acid (HAA) measured in plasma at 2 time points. Partial Spearman's correlation, generalized additive models, and receiver operating characteristic (ROC) analysis were used to assess associations of kynurenines with PLP.
  
  
  RESULTS
  Ratios HK:XA, HK:HAA, and HK:KA showed markedly stronger negative correlations with PLP than did HK alone (Spearman's ρ = -0.36, -0.29, and -0.31 compared with -0.18, respectively). All associations were nonlinear, with the strongest relation at low PLP. In the ROC analysis, areas under the curve for discriminating low PLP (less than the fifth percentile; 18.6 nmol/L) were 0.78, 0.78, and 0.74, respectively, compared with 0.65 for HK. Oral treatment with 40 mg pyridoxin hydrochloride for 28 d reduced the ratios by up to 60%, with strongest reductions for subjects with low plasma PLP at baseline. Whereas HK was associated with kidney function and several inflammatory markers, such associations were abolished or attenuated for the ratios.
  
  
  CONCLUSIONS
  Plasma values of HK:XA and HK:HAA, which are substrate-product pairs for kynurenine transaminase and kynureninase, respectively, may reflect the intracellular availability of the cofactor (PLP) and, therefore, present as potential markers of functional vitamin B-6 status.
authors.affiliation: Bevital A/S, Laboratoriebygget, Bergen, Norway and Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.
authors.forename: Arve
authors.initials: A
authors.lastname: Ulvik
authors.forename: Despoina
authors.initials: D
authors.lastname: Theofylaktopoulou
authors.forename: Øivind
authors.initials: Ø
authors.lastname: Midttun
authors.forename: Ottar
authors.initials: O
authors.lastname: Nygård
authors.forename: Simone J P M
authors.initials: SJ
authors.lastname: Eussen
authors.forename: Per M
authors.initials: PM
authors.lastname: Ueland
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000032:analysis*; D000368:Aged; D000375:Aging / Q000097:blood; D015415:Biomarkers / Q000097:blood; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D007737:Kynurenine / Q000031:analogs & derivatives / Q000097:blood*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009664:Norway; D011732:Pyridoxal Phosphate / Q000097:blood*; D011736:Pyridoxine / Q000008:administration & dosage; D012372:ROC Curve; D000637:Transaminases / Q000378:metabolism; D026681:Vitamin B 6 Deficiency / Q000097:blood*; D014977:Xanthurenates / Q000097:blood*
chemical_list: D015415:Biomarkers; D014977:Xanthurenates; D015095:3-Hydroxyanthranilic Acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; C028330:xanthurenic acid; D011732:Pyridoxal Phosphate; D000637:Transaminases; D006867:Hydrolases; C021480:kynureninase; D011736:Pyridoxine