title: Metabolite profile analysis reveals association of vitamin B-6 with metabolites related to one-carbon metabolism and tryptophan catabolism but not with biomarkers of inflammation in oral contraceptive users and reveals the effects of oral contraceptives on these processes.
abstract: BACKGROUND
  The use of oral contraceptives (OCs) has been associated with low plasma pyridoxal 5'-phosphate (PLP). The functional consequences are unclear.
  
  
  OBJECTIVE
  To determine whether functional vitamin B-6 insufficiency occurs in OC users and is attributable to OCs, we investigated the associations of PLP with metabolites of one-carbon metabolism, tryptophan catabolism, and inflammation in OC users, and evaluated the effects of OCs on these metabolites.
  
  
  METHODS
  Plasma metabolite concentrations were measured in 157 OC users (20-40 y of age). Associations between PLP and the metabolites were analyzed through use of generalized additive models and partial least squares-discriminant analysis (PLS-DA). Additionally, data from 111 of the 157 OC users were compared to previously reported data from 11 nonusers, at adequate and low vitamin B-6 status, with use of multivariate ANOVA.
  
  
  RESULTS
  PLP showed significant (P < 0.05) negative nonlinear association with homocysteine, glutathione, and ratios of asymmetric dimethylarginine to arginine, 3-hydroxykynurenine to 3-hydroxyanthranilic acid, and 3-hydroxykynurenine to kynurenic acid. PLS-DA supported these conclusions and identified 3-hydroxykynurenine and the 3-hydroxykynurenine-to-kynurenine ratio as discriminating biomarkers in women with PLP ≤30 nmol/L. Among the many differences, OC users had significantly higher plasma pyridoxal (157% at adequate and 195% at low vitamin B-6 status), 4-pyridoxic acid (154% at adequate and 300% at low vitamin B-6 status), xanthurenic acid (218% at low vitamin B-6 status), 3-hydroxyanthranilic acid (176% at adequate and 166% at low vitamin B-6 status), quinolinic acid (127% at low vitamin B-6 status), and nicotinamide (197% at low vitamin B-6 status). Biomarkers of inflammation were not associated with PLP, and no differences were found between the 2 groups.
  
  
  CONCLUSIONS
  PLP is associated with biomarkers of one-carbon metabolism and tryptophan catabolism but not with biomarkers of inflammation in OC users. Independent of vitamin B-6 status, OCs have effects on metabolites and ratios of one-carbon metabolism and tryptophan catabolism but not on biomarkers of inflammation. This study was registered at clinicaltrials.gov as NCT01128244. The study from which data for nonusers was derived was registered as NCT00877812.
authors.affiliation: Department of Food Science and Human Nutrition.
authors.forename: Luisa
authors.initials: L
authors.lastname: Rios-Avila
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, College of Medicine.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Coats
authors.affiliation: Department of Biostatistics.
authors.forename: Yueh-Yun
authors.initials: YY
authors.lastname: Chi
authors.affiliation: Bevital A/S, Laboratoriebygget, Bergen, Norway; and.
authors.forename: Øivind
authors.initials: Ø
authors.lastname: Midttun
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Per M
authors.initials: PM
authors.lastname: Ueland
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, College of Medicine Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Stacpoole
authors.affiliation: Department of Food Science and Human Nutrition jfgy@ufl.edu.
authors.forename: Jesse F
authors.initials: JF
authors.lastname: Gregory
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D002244:Carbon / Q000378:metabolism; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood*; D007736:Kynurenic Acid / Q000097:blood; D007737:Kynurenine / Q000031:analogs & derivatives / Q000097:blood; D055442:Metabolome; D011732:Pyridoxal Phosphate / Q000097:blood; D014364:Tryptophan / Q000378:metabolism*; D014481:United States; D025101:Vitamin B 6 / Q000097:blood*; D026681:Vitamin B 6 Deficiency / Q000097:blood / Q000139:chemically induced
chemical_list: D015415:Biomarkers; D003278:Contraceptives, Oral, Hormonal; C005045:3-hydroxykynurenine; D007737:Kynurenine; D011732:Pyridoxal Phosphate; D002244:Carbon; D025101:Vitamin B 6; D014364:Tryptophan; D007736:Kynurenic Acid
keywords: metabolite profile; one-carbon; oral contraceptives; tryptophan; vitamin B-6