Intake and biomarkers of folate and folic acid as determinants of chemotherapy-induced toxicities in patients with colorectal cancer: a cohort study.

BACKGROUND: Capecitabine is an oral chemotherapeutic drug showing antitumor activity through inhibition of thymidylate synthase, an enzyme involved in folate metabolism. There are concerns about the high intake of certain vitamins, and specifically folate, during chemotherapy with capecitabine. Whether folate or folic acid, the synthetic variant of the vitamin, impact treatment toxicity remains unclear. OBJECTIVE: We studied associations between intake and biomarkers of folate as well as folic acid and toxicities in patients with colorectal cancer (CRC) receiving capecitabine. METHODS: Within the prospective COLON (Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that influence recurrence, survival, and quality of life) cohort, 290 patients with stage II to III CRC receiving capecitabine were identified. Dietary and supplemental intake of folate and folic acid were assessed at diagnosis and during chemotherapy using questionnaires (available for 280 patients). Plasma folate and folic acid levels were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) and were available for 212 patients. Toxicities were defined as toxicity-related modifications of treatment, including dose reductions, regimen switches, and early discontinuation. Associations of intake and biomarkers of folate and folic acid with toxicities were determined using Cox proportional hazards regression adjusted for age and sex. RESULTS: In total, 153 (53%) patients experienced toxicities leading to modification of capecitabine treatment. Folate intake and plasma folate levels were not associated with risk of toxicities. However, use of folic acid-containing supplements during treatment (hazard ratio (HR) 1.81 and 95% confidence interval (CI) 1.15-2.85) and presence of folic acid in plasma at diagnosis (HR 2.09, 95% CI: 1.24, 3.52) and during treatment (HR 2.31, 95% CI: 1.29, 4.13) were associated with an increased risk of toxicities. CONCLUSIONS: This study suggests a potential association between folic acid and capecitabine-induced toxicities, providing a rationale to study diet-drug interactions and raise further awareness of the use of dietary supplements during oncological treatment. CLINICAL TRIAL DETAILS: This trial was registered at clinicaltrials.gov as NCT03191110.

Longitudinal associations of macronutrient and micronutrient intake with plasma kynurenines in colorectal cancer survivors up to 12 months posttreatment.

BACKGROUND: The tryptophan-kynurenine pathway is increasingly recognized to play a role in health-related quality of life (HRQoL) after cancer. Because tryptophan is an essential amino acid, and vitamins and minerals act as enzymatic cofactors in the tryptophan-kynurenine pathway, a link between diet and kynurenines is plausible. OBJECTIVES: This study aimed to investigate the longitudinal associations of macronutrient and micronutrient intake with metabolites of the kynurenine pathway in colorectal cancer (CRC) survivors up to 12 mo posttreatment. METHODS: In a prospective cohort of stage I-III CRC survivors (n = 247), repeated measurements were performed at 6 wk, 6 mo, and 12 mo posttreatment. Macronutrient and micronutrient intake was measured by 7-d dietary records. Plasma concentrations of tryptophan and kynurenines were analyzed using liquid chromatography tandem mass spectrometry (LC/MS-MS). Longitudinal associations were analyzed using linear mixed models adjusted for sociodemographic, clinical, and lifestyle factors. RESULTS: After adjustment for multiple testing, higher total protein intake was positively associated with kynurenic acid (KA) (ß as standard deviation [SD] change in KA concentration per 1 SD increase in total protein intake: 0.12; 95% CI: 0.04, 0.20), xanthurenic acid (XA) (standardized ß: 0.22; 95% CI: 0.11, 0.33), 3-hydroxyanthranilic acid (HAA) (standardized ß: 0.15; 95% CI: 0.04, 0.27) concentrations, and the kynurenic acid-to-quinolinic acid ratio (KA/QA) (standardized ß: 0.12; 95% CI: 0.02,0.22). In contrast, higher total carbohydrate intake was associated with lower XA concentrations (standardized ß: -0.18; 95% CI: -0.30, -0.07), a lower KA/QA (standardized ß: -0.23; 95% CI: -0.34, -0.13), and a higher kynurenine-to-tryptophan ratio (KTR) (standardized ß: 0.20; 95% CI: 0.10, 0.30). Higher fiber intake was associated with a higher KA/QA (standardized ß: 0.11; 95% CI: 0.02, 0.21) and a lower KTR (standardized ß: -0.12; 95% CI: -0.20, -0.03). Higher total fat intake was also associated with higher tryptophan (Trp) concentrations (standardized ß: 0.18; 95% CI: 0.06, 0.30) and a lower KTR (standardized ß: -0.13; 95% CI: -0.22, -0.03). For micronutrients, positive associations were observed for zinc with XA (standardized ß: 0.13; 95% CI: 0.04, 0.21) and 3-hydroxykynurenine (HK) (standardized ß: 0.12; 95% CI: 0.03, 0.20) concentrations and for magnesium with KA/QA (standardized ß: 0.24; 95% CI: 0.13, 0.36). CONCLUSIONS: Our findings show that intake of several macronutrients and micronutrients is associated with some metabolites of the kynurenine pathway in CRC survivors up to 12 mo posttreatment. These results may be relevant for enhancing HRQoL after cancer through potential diet-induced changes in kynurenines. Further studies are necessary to confirm our findings.

Clinical and biochemical impact of vitamin B6 deficiency in primary sclerosing cholangitis before and after liver transplantation.

BACKGROUND AND AIMS: We previously demonstrated that people with primary sclerosing cholangitis (PSC) had reduced gut microbial capacity to produce active vitamin B6 (pyridoxal 5'-phosphate [PLP]), which corresponded to lower circulating PLP levels and poor outcomes. Here, we define the extent and biochemical and clinical impact of vitamin B6 deficiency in people with PSC from several centers before and after liver transplantation (LT). METHODS: We used targeted liquid chromatography-tandem mass spectrometry to measure B6 vitamers and B6-related metabolic changes in blood from geographically distinct cross-sectional cohorts totaling 373 people with PSC and 100 healthy controls to expand on our earlier findings. Furthermore, we included a longitudinal PSC cohort (n = 158) sampled prior to and serially after LT, and cohorts of people with inflammatory bowel disease (IBD) without PSC (n = 51) or with primary biliary cholangitis (PBC) (n = 100), as disease controls. We used Cox regression to measure the added value of PLP to predict outcomes before and after LT. RESULTS: In different cohorts, 17-38% of people with PSC had PLP levels below the biochemical definition of a vitamin B6 deficiency. The deficiency was more pronounced in PSC than in IBD without PSC and PBC. Reduced PLP was associated with dysregulation of PLP-dependent pathways. The low B6 status largely persisted after LT. Low PLP independently predicted reduced LT-free survival in both non-transplanted people with PSC and in transplant recipients with recurrent disease. CONCLUSIONS: Low vitamin B6 status with associated metabolic dysregulation is a persistent feature of PSC. PLP was a strong prognostic biomarker for LT-free survival both in PSC and recurrent disease. Our findings suggest that vitamin B6 deficiency modifies the disease and provides a rationale for assessing B6 status and testing supplementation. IMPACT AND IMPLICATIONS: We previously found that people with PSC had reduced gut microbial potential to produce essential nutrients. Across several cohorts, we find that the majority of people with PSC are either vitamin B6 deficient or have a marginal deficiency, which remains prevalent even after liver transplantation. Low vitamin B6 levels strongly associate with reduced liver transplantation-free survival as well as deficits in biochemical pathways dependent on vitamin B6, suggesting that the deficiency has a clinical impact on the disease. The results provide a rationale for measuring vitamin B6 and to investigate whether vitamin B6 supplementation or modification of the gut microbial community can help improve outcomes for people with PSC.

A comparison of complementary measures of vitamin B6 status, function, and metabolism in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

BACKGROUND: Vitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5'-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health. OBJECTIVES: We explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics. MEDTHODS: Dietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP. RESULTS: In total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers. CONCLUSIONS: We found that 5 different markers, capturing different aspects of vitamin B6-related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors.

Circulating B-vitamin biomarkers and B-vitamin supplement use in relation to quality of life in patients with colorectal cancer: results from the FOCUS consortium.

BACKGROUND: B vitamins have been associated with the risk and progression of colorectal cancer (CRC), given their central roles in nucleotide synthesis and methylation, yet their association with quality of life in established CRC is unclear. OBJECTIVES: To investigate whether quality of life 6 months postdiagnosis is associated with: 1) circulating concentrations of B vitamins and related biomarkers 6 months postdiagnosis; 2) changes in these concentrations between diagnosis and 6 months postdiagnosis; 3) B-vitamin supplement use 6 months postdiagnosis; and 4) changes in B-vitamin supplement use between diagnosis and 6 months postdiagnosis. METHODS: We included 1676 newly diagnosed stage I-III CRC patients from 3 prospective European cohorts. Circulating concentrations of 9 biomarkers related to the B vitamins folate, riboflavin, vitamin B6, and cobalamin were measured at diagnosis and 6 months postdiagnosis. Information on dietary supplement use was collected at both time points. Health-related quality of life (global quality of life, functioning scales, and fatigue) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 6 months postdiagnosis. Confounder-adjusted linear regression analyses were performed, adjusted for multiple testing. RESULTS: Higher pyridoxal 5'-phosphate (PLP) was cross-sectionally associated with better physical, role, and social functioning, as well as reduced fatigue, 6 months postdiagnosis. Associations were observed for a doubling in the hydroxykynurenine ratio [3-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3-hydroxyanthranilic acid + anthranilic acid); an inverse marker of vitamin B6] and both reduced global quality of life (ß = -3.62; 95% CI: -5.88, -1.36) and worse physical functioning (ß = -5.01; 95% CI: -7.09, -2.94). Dose-response relations were observed for PLP and quality of life. No associations were observed for changes in biomarker concentrations between diagnosis and 6 months. Participants who stopped using B-vitamin supplements after diagnosis reported higher fatigue than nonusers. CONCLUSIONS: Higher vitamin B6 status was associated with better quality of life, yet limited associations were observed for the use of B-vitamin supplements. Vitamin B6 needs further study to clarify its role in relation to quality of life.

Performance of plasma trigonelline as a marker of coffee consumption in an epidemiologic setting.

Background: Coffee is a widely consumed beverage, and studies suggest that drinking coffee has beneficial health effects. The phytohormone trigonelline is present in large amounts in coffee beans, and circulating concentrations of trigonelline have been shown to be positively related to dietary intake of coffee and to increase significantly after the consumption of a bolus dose of coffee. Objective: We cross-sectionally investigated the utility of plasma trigonelline as a marker of coffee consumption in an epidemiologic setting. We secondarily investigated if coffee intake is related to plasma concentrations of vitamin B-3 (niacin) forms. Design: In a Norwegian cohort of 3503 participants, we combined questionnaire data on the number of cups of coffee consumed per day with plasma trigonelline to evaluate trigonelline as a marker of coffee intake. The suitability of plasma trigonelline to discriminate those not consuming from those consuming coffee was investigated by receiver operating characteristic (ROC) analysis. Plasma collected at 2 time points 1 y apart was used to determine the within-person reproducibility of trigonelline. Results: We found that plasma trigonelline concentrations increased strongly with increasing amounts of coffee consumed. ROC analysis showed that trigonelline had an area under the curve of 0.92 (95% CI: 0.90, 0.94) for distinguishing coffee abstainers from coffee drinkers. Plasma trigonelline had a good within-person reproducibility (0.66; 95% CI: 0.64, 0.68) for samples collected 1 y apart. The amount of coffee consumed was not associated with plasma concentrations of the niacin vitamers nicotinamide and N1-methylnicotinamide. Conclusions: Plasma trigonelline performs well as a marker of coffee intake. Data used in this study were derived from the clinical trial registered at www.clinicaltrials.gov as NCT00354081.

Cobalamin and Folate Status among Breastfed Infants in Bhaktapur, Nepal.

Cobalamin and folate are crucial micronutrients during infancy and they are required for growth and cognitive development. Due to the monotonous and predominantly vegetarian-based complementary feeding and poor maternal micronutrient status, infants from low- and middle-income countries are susceptible to cobalamin deficiency. However, data on plasma cobalamin and folate and the functional markers methylmalonic acid and total homocysteine from breastfed infants in Nepal are still needed. We collected plasma samples from 316 6⁻11-month-old breastfed infants with a length-for-age of less than minus one z-score and analyzed blood for plasma folate, cobalamin, methylmalonic acid and total homocysteine concentrations. Cobalamin deficiency (plasma cobalamin 10 µmol/L) and methylmalonic acid (>0.28 µmol/L) indicating functional cobalamin deficiency were found among 53% and 75% of the infants, respectively. Based on a combined indicator of cobalamin status, 58% were found to have low cobalamin status. However, folate deficiency (.

Circulating concentrations of biomarkers and metabolites related to vitamin status, one-carbon and the kynurenine pathways in US, Nordic, Asian, and Australian populations.

Background: Circulating concentrations of biomarkers that are related to vitamin status vary by factors such as diet, fortification, and supplement use. Published biomarker concentrations have also been influenced by the variation across laboratories, which complicates a comparison of results from different studies.Objective: We robustly and comprehensively assessed differences in biomarkers that are related to vitamin status across geographic regions.Design: The trial was a cross-sectional study in which we investigated 38 biomarkers that are related to vitamin status and one-carbon and tryptophan metabolism in serum and plasma from 5314 healthy control subjects representing 20 cohorts recruited from the United States, Nordic countries, Asia, and Australia, participating in the Lung Cancer Cohort Consortium. All samples were analyzed in a centralized laboratory.Results: Circulating concentrations of riboflavin, pyridoxal 5'-phosphate, folate, vitamin B-12, all-trans retinol, 25-hydroxyvitamin D, and α-tocopherol as well as combined vitamin scores that were based on these nutrients showed that the general B-vitamin concentration was highest in the United States and that the B vitamins and lipid soluble vitamins were low in Asians. Conversely, circulating concentrations of metabolites that are inversely related to B vitamins involved in the one-carbon and kynurenine pathways were high in Asians. The high B-vitamin concentration in the United States appears to be driven mainly by multivitamin-supplement users.Conclusions: The observed differences likely reflect the variation in intake of vitamins and, in particular, the widespread multivitamin-supplement use in the United States. The results provide valuable information about the differences in biomarker concentrations in populations across continents.

Inflammation, vitamin B6 and related pathways.

The active form of vitamin B6, pyridoxal 5'-phosphate (PLP), serves as a co-factor in more than 150 enzymatic reactions. Plasma PLP has consistently been shown to be low in inflammatory conditions; there is a parallel reduction in liver PLP, but minor changes in erythrocyte and muscle PLP and in functional vitamin B6 biomarkers. Plasma PLP also predicts the risk of chronic diseases like cardiovascular disease and some cancers, and is inversely associated with numerous inflammatory markers in clinical and population-based studies. Vitamin B6 intake and supplementation improve some immune functions in vitamin B6-deficient humans and experimental animals. A possible mechanism involved is mobilization of vitamin B6 to the sites of inflammation where it may serve as a co-factor in pathways producing metabolites with immunomodulating effects. Relevant vitamin B6-dependent inflammatory pathways include vitamin B6 catabolism, the kynurenine pathway, sphingosine 1-phosphate metabolism, the transsulfuration pathway, and serine and glycine metabolism.

Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls.

BACKGROUND: Folate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear. OBJECTIVE: To investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade. DESIGN, SETTING, AND PARTICIPANTS: A study was performed with a nested case-control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incident PCa and subtype by stage and grade. RESULTS AND LIMITATIONS: Higher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02-1.26], ptrend=0.018, for folate and 1.12 [95% CI, 1.01-1.25], ptrend=0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity<0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28-4.12]; ptrend=0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (pheterogeneity>0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation. CONCLUSIONS: The association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation. PATIENT SUMMARY: Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.

Circulating B-vitamins and smoking habits are associated with serum polyunsaturated Fatty acids in patients with suspected coronary heart disease: a cross-sectional study.

The long-chain polyunsaturated fatty acids are considered to be of major health importance, and recent studies indicate that their endogenous metabolism is influenced by B-vitamin status and smoking habits. We investigated the associations of circulating B-vitamins and smoking habits with serum polyunsaturated fatty acids among 1,366 patients who underwent coronary angiography due to suspected coronary heart disease at Haukeland University Hospital, Norway. Of these, 52% provided information on dietary habits by a food frequency questionnaire. Associations were assessed using partial correlation (Spearman's rho). In the total population, the concentrations of most circulating B-vitamins were positively associated with serum n-3 polyunsaturated fatty acids, but negatively with serum n-6 polyunsaturated fatty acids. However, the associations between B-vitamins and polyunsaturated fatty acids tended to be weaker in smokers. This could not be solely explained by differences in dietary intake. Furthermore, plasma cotinine, a marker of recent nicotine exposure, showed a negative relationship with serum n-3 polyunsaturated fatty acids, but a positive relationship with serum n-6 polyunsaturated fatty acids. In conclusion, circulating B-vitamins are, in contrast to plasma cotinine, generally positively associated with serum n-3 polyunsaturated fatty acids and negatively with serum n-6 polyunsaturated fatty acids in patients with suspected coronary heart disease. Further studies should investigate whether B-vitamin status and smoking habits may modify the clinical effects of polyunsaturated fatty acid intake.

Evidence for increased catabolism of vitamin B-6 during systemic inflammation.

BACKGROUND: Plasma concentrations of PL 5'-phosphate (PLP), which is the active coenzyme form of vitamin B-6, are reduced during inflammation. The underlying mechanisms may include altered tissue distribution or increased catabolism via pyridoxal (PL) to pyridoxic acid (PA). Recently, we showed that catabolic enzyme activity could be assessed by substrate product ratios measured in plasma. OBJECTIVE: We evaluated the ratios PA:PL, PA:PLP, and PA:(PL + PLP) as possible markers of vitamin B-6 catabolism. DESIGN: Cross-sectional and longitudinal data were derived from the Western Norway B-Vitamin Intervention Trial. We analyzed associations of ratios with inflammatory markers and other clinical variables by using multiple linear regression and partial correlation. In addition, intraclass correlation coefficients (ICCs) were used to assess the ability of plasma indexes to differentiate between subjects. RESULTS: PA:(PL + PLP) had the highest ICC of all vitamin B-6 metabolites and ratios tested. In regression models, the inflammatory markers C-reactive protein, white blood cell count, neopterin, and kynurenine:tryptophan collectively accounted for 28% of the total and > 90% of the explained variation in PA:(PL + PLP). For individual B-6 metabolites, corresponding numbers were 19-25% and 20-44%, respectively, with vitamin supplement intake, smoking, and kidney function (estimated glomerular filtration rate) as additional predictors. In an analysis of receiver operating characteristics, PA:(PL + PLP) discriminated high inflammatory concentrations with an area under the curve (95% CI) of 0.85 (0.81, 0.89). CONCLUSIONS: Broad-specificity enzymes upregulated to reduce oxidative and aldehyde stress could explain increased catabolism of vitamin B-6 during inflammation. The ratio PA:(PL + PLP) may provide novel insights into pathologic processes and potentially predict risk of future disease.

Association of plasma B-6 vitamers with systemic markers of inflammation before and after pyridoxine treatment in patients with stable angina pectoris.

BACKGROUND: A negative association between systemic markers of inflammation and plasma vitamin B-6 has been observed in population-based and patient cohorts; however, vitamin B-6 (pyridoxine) treatment has mostly failed to improve inflammatory indexes. OBJECTIVE: We aimed to assess the effect of pyridoxine treatment on B-6 vitamer and inflammatory marker relations. DESIGN: We measured pyridoxal 5'-phosphate (PLP), pyridoxal, 4-pyridoxic acid (PA), C-reactive protein (CRP), neopterin, and the kynurenine-to-tryptophan ratio (KTR) in plasma and the white blood cell count (WBC). A partial Spearman's correlation was used to assess associations of B-6 vitamers with inflammatory markers before and after daily treatment with 40 mg pyridoxine hydrochloride. Generalized additive models and segmented regression analysis were used for nonlinear relations. RESULTS: A 9-60-fold increase in B-6 vitamer concentrations over baseline values was observed after 28 d of treatment with pyridoxine. PLP was negatively associated with all 4 inflammatory markers at baseline and, predominantly, with CRP and KTR at day 28. The catabolite PA was positively associated with neopterin and KTR before and after treatment. The dose-response relation between CRP and B-6 vitamers at day 28 was nonlinear, with an increased steepness of slope at CRP >7 mg/L. Finally, changes in B-6 vitamer concentrations were correlated with changes in inflammatory marker concentrations over a time span of 4 wk. CONCLUSIONS: The associations between plasma vitamin B-6 and inflammatory markers were preserved or even increased after pyridoxine treatment. The results suggest that the acute phase and activated cellular immunity are associated with increased cellular uptake and catabolism of vitamin B-6, respectively.

Low plasma vitamin B-6 status affects metabolism through the kynurenine pathway in cardiovascular patients with systemic inflammation.

It is unclear whether reduced plasma pyridoxal 5'-phosphate (PLP) during inflammation reflects an altered distribution or increased requirement of vitamin B-6 that may impair overall vitamin B-6 status in tissues. In plasma from 3035 patients undergoing coronary angiography for suspected coronary heart disease, we investigated if plasma concentrations of any metabolites in the kynurenine pathway, which depend on PLP as cofactor, may serve as metabolic marker(s) of vitamin B-6 status. We also examined the association of vitamin B-6 status with serum or plasma concentrations of several inflammatory markers. Among the kynurenines, only 3-hydroxykynurenine (HK) was inversely related to PLP and showed a positive relation to 4 investigated inflammatory markers. A segmented relationship was observed between PLP and HK, with a steep slope at PLP concentrations < 18.4 nmol/L, corresponding to the 5th percentile, and an almost zero slope at higher PLP concentrations. Low PLP and the steep PLP-HK slope were essentially confined to participants with 1 or more inflammatory markers in the upper tertile. Oral supplementation with pyridoxine hydrochloride (40 mg/d) for 1 mo increased plasma PLP 8-fold, reduced the geometric mean (95% CI) of HK from 29.5 to 20.2 nmol/L (P < 0.001), and abolished the steep segment of the PLP-HK curve. The steep inverse relationship of plasma PLP with HK at low plasma PLP and the lowering of HK by pyridoxine suggest plasma HK as a metabolic marker of vitamin B-6 status. Thus, low plasma PLP during inflammation may reflect impaired cellular vitamin B-6 status, as indicated by the concurrent increase in plasma HK.

Infant birth size is not associated with maternal intake and status of folate during the second trimester in Norwegian pregnant women.

Maternal folate status and smoking are potentially strong risk factors for infant birth size. We assessed the association of several folate indicators and smoking with birth outcomes in a subsample of participants in the Norwegian Mother and Child Cohort Study, consisting of 2934 singleton pregnancies in 2002-2003. Blood plasma folate and cotinine concentrations and self-reported intake of food folate and supplemental folic acid were measured during the second trimester (median 18 wk). Birth outcomes included gestational age, infant birth weight, head circumference, crown-heel length, and small for gestational age (SGA). Mean total dietary folate intake from foods (mean 268.0 microg/d) and supplements (mean 187.7 microg/d) was 455.7 microg/d. Smokers (plasma cotinine > or = 85 nmol/L) had substantially lower supplemental folic acid intake than nonsmokers, but they did not differ regarding folate intake from food only. Nevertheless, smoking was correlated with plasma folate both before and after adjusting for total dietary folate intake (both P < 0.001). We found no significant associations of food folate intake, supplemental folic acid use, total dietary folate intake, or plasma folate with the various birth outcomes after adjustment for potential confounders. Consistent with previous studies, infant birth size was strongly predicted by maternal smoking (adjusted odds ratio for SGA: 2.3; 95% CI: 1.6, 3.3). This study of well-nourished Norwegian pregnant women suggests that dietary folate and plasma folate during the second trimester are not risk factors for infant birth size.

Dietary patterns, food groups, and nutrients as predictors of plasma choline and betaine in middle-aged and elderly men and women.

BACKGROUND: Choline and betaine are linked to phospholipid and one-carbon metabolism. Blood concentrations or dietary intake of these quaternary amines have been related to the risk of chronic diseases, including cardiovascular disease and the metabolic syndrome. OBJECTIVE: We aimed to determine dietary predictors of plasma choline and betaine among middle-aged and elderly subjects recruited from an area without folic acid fortification. DESIGN: This is a population-based study of 5812 men and women aged 47-49 and 71-74 y, within the Hordaland Health Study cohort. Plasma concentrations per increasing quartile of intake of foods, beverages, and nutrients were assessed by multiple linear regression analysis, and dietary patterns were assessed by factor analysis. RESULTS: Plasma choline was predicted by egg consumption (0.16 micromol/L; P < 0.0001) and cholesterol intake (0.16 micromol/L; P < 0.0001), and betaine was predicted by consumption of high-fiber bread (0.65 micromol/L; P < 0.0001); high-fat dairy products (-0.70 micromol/L; P < 0.0001); complex carbohydrates, fiber, folate, and thiamine (0.66-1.44 micromol/L; P

Coffee consumption and circulating B-vitamins in healthy middle-aged men and women.

BACKGROUND: Coffee consumption has been associated with several risk factors for coronary heart disease, including increased cholesterol, increased blood pressure, and increased plasma total homocysteine (tHcy). tHcy is determined by several B-vitamins. However, reports about the association between coffee intake and B-vitamin status are few. METHODS: We measured plasma B-vitamins and tHcy in a cohort of 10,601 healthy, middle-aged Norwegian men and women. Information about lifestyle factors, including coffee consumption, smoking, alcohol use, height, and weight, was obtained by interview. RESULTS: Coffee consumption was dose-dependently associated with reduced plasma B-vitamin concentrations. Compared with coffee abstainers, individuals drinking >or=4 cups/day had 11.7% (P < 0.001), 14.1% (P < 0.001), and 5.5% (P = 0.01) lower plasma concentrations of folate, pyridoxal phosphate, and riboflavin, respectively, and the mean tHcy concentration was 6.8% (P < 0.001) higher. Quantile regression analysis showed essentially no difference in B-vitamin concentrations between coffee consumption categories at low vitamin concentrations but a progressive increase in the difference at higher concentrations. This pattern of differences (effect profile) was found independently of smoking status, alcohol intake, and sex. The decrease in folate explained approximately half of the increase in tHcy. CONCLUSIONS: Coffee consumption was associated with reduced circulating B-vitamin concentrations. The observed effect profiles indicated that coffee consumption preferentially affected the upper, but not the lower, part of the B-vitamin concentration distributions. We hypothesize that coffee consumption may increase the loss of surplus B-vitamins by excretion in urine.