Tryptophan catabolites as metabolic markers of vitamin B-6 status evaluated in cohorts of healthy adults and cardiovascular patients

Abstract

Vitamin B-6 status is routinely measured as pyridoxal 5'-phosphate (PLP) in plasma. Low concentrations of PLP are associated with rheumatic, cardiovascular, and neoplastic diseases. We have previously shown that vitamin B-6 status affects the kynurenine (Kyn) pathway of tryptophan (Trp) catabolism. This study aimed to comprehensively evaluate the use of Kyns as potential markers of functional vitamin B-6 status across 2 large cohorts. We measured circulating concentrations of the first 6 metabolites in the Trp catabolic pathway by LC-MS-MS in the community-based Hordaland Health Study (HUSK; n=7017) and cardiovascular patient-based Western Norway Coronary Angiography Cohort (WECAC; n=4161). Cross-sectional and longitudinal associations of plasma PLP with Kyns were estimated using linear and nonlinear regression-based methods. 3'-Hydroxykynurenine (HK), a substrate, and all 4 products formed directly by the PLP-dependent enzymes kynurenine transaminase and kynureninase contributed to the explanation of circulating PLP in multivariable-adjusted regression models. The construct HK:(kynurenic acid+xanthurenic acid+3'-hydroxyanthranilic acid+anthranilic acid), termed HK ratio (HKr), was related to plasma PLP with standardized regression coefficients (95% CIs) of -0.47 (-0.49, -0.45) and -0.46 (-0.49, -0.43) in HUSK and WECAC, respectively. Across strata of cohort and sex, HKr was 1.3- to 2.7-fold more sensitive, but also 1.7- to 2.9-fold more specific to changes in PLP than a previously proposed marker, HK:xanthurenic acid. Notably, the association was strongest at PLP concentrations<∼20 nmol/L, a recognized threshold for vitamin B-6 deficiency. Finally, PLP and HKr demonstrated highly sex-specific and corroborating associations with age. The results demonstrate that by combining 5 metabolites in the Kyn pathway into a simple index, HKr, a sensitive and specific indicator of intracellular vitamin B-6 status is obtained. The data also underscore the merit of evaluating alterations in Kyn metabolism when investigating vitamin B-6 and health.