Folate catabolites in spot urine as non-invasive biomarkers of folate status during habitual intake and folic acid supplementation.

Folate status, as reflected by red blood cell (RCF) and plasma folates (PF), is related to health and disease risk. Folate degradation products para-aminobenzoylglutamate (pABG) and para-acetamidobenzoylglutamate (apABG) in 24 hour urine have recently been shown to correlate with blood folate. Since blood sampling and collection of 24 hour urine are cumbersome, we investigated whether the determination of urinary folate catabolites in fasted spot urine is a suitable non-invasive biomarker for folate status in subjects before and during folic acid supplementation. Immediate effects of oral folic acid bolus intake on urinary folate catabolites were assessed in a short-term pre-study. In the main study we included 53 healthy men. Of these, 29 were selected for a 12 week folic acid supplementation (400 µg). Blood, 24 hour and spot urine were collected at baseline and after 6 and 12 weeks and PF, RCF, urinary apABG and pABG were determined. Intake of a 400 µg folic acid bolus resulted in immediate increase of urinary catabolites. In the main study pABG and apABG concentrations in spot urine correlated well with their excretion in 24 hour urine. In healthy men consuming habitual diet, pABG showed closer correlation with PF (rs = 0.676) and RCF (rs = 0.649) than apABG (rs = 0.264, ns and 0.543). Supplementation led to significantly increased folate in plasma and red cells as well as elevated urinary folate catabolites, while only pABG correlated significantly with PF (rs = 0.574) after 12 weeks. Quantification of folate catabolites in fasted spot urine seems suitable as a non-invasive alternative to blood or 24 hour urine analysis for evaluation of folate status in populations consuming habitual diet. In non-steady-state conditions (folic acid supplementation) correlations between folate marker (RCF, PF, urinary catabolites) decrease due to differing kinetics

Prevention of Neural-Tube Defects with Periconceptional Folic Acid, Methylfolate, or Multivitamins?

Background/Aims: To review the main results of intervention trials which showed the efficacy of periconceptional folic acid-containing multivitamin and folic acid supplementation in the prevention of neural-tube defects (NTD). Methods and Results: The main findings of 5 intervention trials are known: (i) the efficacy of a multivitamin containing 0.36 mg folic acid in a UK nonrandomized controlled trial resulted in an 83-91% reduction in NTD recurrence, while the results of the Hungarian (ii) randomized controlled trial and (iii) cohort-controlled trial using a multivitamin containing 0.8 mg folic acid showed 93 and 89% reductions in the first occurrence of NTD, respectively. On the other hand, (iv) another multicenter randomized controlled trial proved a 71% efficacy of 4 mg folic acid in the reduction of recurrent NTD, while (v) a public health-oriented Chinese-US trial showed a 41-79% reduction in the first occurrence of NTD depending on the incidence of NTD. Conclusions: Translational application of these findings could result in a breakthrough in the primary prevention of NTD, but so far this is not widely applied in practice. The benefits and drawbacks of 4 main possible uses of periconceptional folic acid/multivitamin supplementation, i.e. (i) dietary intake, (ii) periconceptional supplementation, (iii) flour fortification, and (iv) the recent attempt for the use of combination of oral contraceptives with 6S-5-methytetrahydrofolate (methylfolate), are discussed. Obviously, prevention of NTD is much better than the frequent elective termination of pregnancies after prenatal diagnosis of NTD fetuses

Дослідження рівня фолатів у плазмі крові під дією [6S]-5-МТГФ в жінок із поліморфізмом гена МТГФР 677Ц→Т з різним типом успадкування

Background and purpose: 5,10-Methylenetetrahydrofolate reductase is responsible for the synthesis of 5-methyltetrahydrofolate (5-MTHF). The 677C→T mutation of 5,10-Methylenetetrahydrofolate reductase reduces the activity of this enzyme. The aim of this study was, first, to compare pharmacokinetic parameters of [6S]-5-MTHF and folic acid in women with the homozygous (TT) and wild-type (CC) 677C→T mutation, and second, to explore genotype differences. The metabolism of [6S]-5-MTHF and folic acid was evaluated by measuring plasma folate derivatives.Experimental approach: Healthy females (TT, n = 16; CC, n = 8) received a single oral dose of folic acid (400 microg) and [6S]-5-MTHF (416 microg) in a randomized crossover design.Plasma folate was measured up to 8 h after supplementation. Concentration-time-profile (area under the curve of the plasma folate concentration vs. time), maximum concentration (Cmax) and time-to-reach-maximum (tmax) were calculated.Key results: Area under the curve of the plasma folate concentration vs. time and Cmax were significantly higher, and tmax significantly shorter for [6S]-5-MTHF compared with folic acid in both genotypes. A significant difference between the genotypes was observed for tmax after folic acid only (p < 0.05). Plasma folate consisted essentially of 5-MTHF irrespective of the folate form given. Unmetabolized folic acid in plasma occurs regularly following folic acid supplementation, but rarely with [6S]-5-MTHF.Conclusions and implications: These data suggest that [6S]-5-MTHF increases plasma folate more effectively than folic acid irrespective of the 677C→T mutation of the 5,10-Methylenetetrahydrofolate reductase. This natural form of folate could be an alternative to folic acid supplementation or fortification.Предпосылки и цель: фермент 5,10-метилентетрагидрофолатредуктаза отвечает за синтез 5-метилтетрагидрофолата (5-МТГФ). Мутация гена 677Ц→T 5,10-метилентетрагидрофолатредуктазы снижает активность этого фермента. Целью данного исследования было, во-первых, сравнить фармакокинетические параметры [6S]- 5-МТГФ и фолиевой кислоты у женщин с гомозиготным типом наследования (TT) и аллелями дикого типа (CC) полиморфизма гена 677Ц→T, а во-вторых, изучить генетические различия. Метаболизм [6S]-5-MTHF и фолиевой кислоты оценивали путем измерения производных фолатов в плазме крови.Экспериментальный подход: здоровые женщины (TT, n = 16; CC, n = 8) получили однократную пероральную дозу фолиевой кислоты (400 мкг) и [6S]-5-МГТФ (416 мкг) в рандомизированном перекрестном проекте. Содержание фолатов в плазме крови измеряли через 8 ч после приема. Был рассчитан профиль концентрация-время (площадь под кривой концентрации фолатов в плазме крови в зависимости от времени), максимальное содержание фолатов (Cmax) и время, необходимое для достижения максимального общего сывороточного уровня фолатов (tmax).Основные результаты: площадь под кривой концентрации фолатов в плазме крови в зависимости от времени и Cmax была значительно выше, а tmax значительно короче для [6S]-5-МГТФ по сравнению с фолиевой кислотой в обоих исследуемых генотипах. Значительная разница между генотипами наблюдалась только для tmax после приема фолиевой кислоты (p < 0,05). Содержание фолатов в плазме крови состояло в основном из 5-МГТФ независимо от формы фолата. Неметаболизированная фолиевая кислота в плазме крови регулярно появляется после приема фолиевой кислоты, но редко – после добавления [6S]-5-МГТФ.Выводы: данные, полученные в результате исследования, позволяют предположить, что прием [6S]-5-МГТФ повышает общее содержание фолатов в плазме крови в большей степени, чем фолиевая кислота, независимо от генотипа мутации гена 677Ц→T 5,10-метилентетрагидрофолатредуктазы. Эта натуральная форма фолата может бать альтернативой добавкам с фолиевой кислотой или обогащению ею пищи.Передумови і мета: фермент 5,10-метилентетрагідрофолатредуктаза відповідає за синтез 5-метилтетрагідрофолату (5-МТГФ). Мутація гена 677Ц→T 5,10-метилентетрагідрофолатредуктази знижує активність цього ферменту. Метою даного дослідження було, по-перше, порівняти фармакокінетичні параметри [6S]-5-МТГФ і фолієвої кислоти в жінок із гомозиготним типом успадкування (TT) і алелями дикого типу (CC) поліморфізму гена 677Ц→T, а, по-друге, вивчити генетичні відмінності.Метаболізм [6S]-5-MTHF і фолієвої кислоти оцінювали шляхом вимірювання похідних фолатів у плазмі крові.Експериментальний підхід: здорові жінки (TT, n = 16; CC, n = 8) отримали одноразову пероральну дозу фолієвої кислоти (400 мкг) і [6S]-5-МГТФ (416 мкг) у рандомізованому перехресному проекті. Вміст фолатів у плазмі крові вимірювали через 8 годин після прийому. Був розрахований профіль концентрація-час (площа під кривою концентрації фолатів у плазмі крові в залежності від часу), максимальний вміст фолатів (Cmax) і час, необхідний для досягнення максимального загального сироваткового рівня фолатів (tmax).Основні результати: площа під кривою концентрації фолатів у плазмі крові в залежності від часу і Cmax була значно вищою, а tmax значно коротшим для [6S]-5-МГТФ у порівнянні з фолієвою кислотою в обох досліджуваних генотипах. Значна різниця між генотипами спостерігалася тільки для tmax після прийому фолієвої кислоти (p < 0,05). Вміст фолатів в плазмі крові складався в основному з 5-МГТФ незалежно від форми фолату. Неметаболізована фолієва кислота в плазмі крові регулярно з’являється після прийому фолієвої кислоти, але рідко – після додавання [6S]-5-МГТФ.Висновки: дані, отримані в результаті дослідження, дозволяють припустити, що прийом [6S]-5-МГТФ підвищує загальний вміст фолатів у плазмі крові більшою мірою, ніж фолієва кислота, незалежно від генотипу мутації гена 677Ц→T 5,10-метилентетрагідрофолатредуктази. Ця натуральна форма фолату може бути альтернативою добавкам із фолієвою кислотою або збагаченню нею їжі

Indicators of overweight and cardiovascular disease risk factors among 11- to 17-year-old boys and girls in Germany.

OBJECTIVE: We analyzed the magnitude of the association between cardiovascular disease (CVD) risk factors and various measures of overweight among adolescents, to determine which indicator of overweight is most relevant for risk assessment. METHODS: 5,546 boys and girls aged 11-17 years participating in the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) were studied. Overweight was assumed when different anthropometric variables exceeded age- and sex-specific 90th percentiles. Blood pressure was measured and blood samples were analyzed for serum total cholesterol, lipoproteins, high-sensitivity C-reactive protein, and glycosylated hemoglobin (HbA1c). RESULTS: In both sexes, overweight was significantly associated with adverse levels of CVD risk factors, except HbA1c. These associations were most pronounced for overweight as defined by waist circumference (WC), waist-to-height ratio (WHtR), or BMI. Between 11% and 37% of the overweight children exceeded the defined cut-offs for individual CVD risk factors, with age- and puberty-adjusted significant odds ratios (95% confidence interval (CI)) in comparison to normal-weight age mates ranging from 1.7 (1.0-3.0) to 6.1 (4.5-8.2). CONCLUSIONS: The findings of this population-based survey suggest that, among adolescents, WC, WHtR, and BMI are easily applicable measures of overweight that appear to be relevant for CVD risk assessment

Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK

Following an introduction of the importance of folates and the rationale for seeking to estimate fractional folate absorption from foods (especially for countries not having a mandatory folic acid fortification policy), scientific papers covering the mechanisms of folate absorption and initial biotransformation are discussed. There appears (post-1983) to be a consensus that physiological doses of folic acid undergo biotransformation in the absorptive cells of the upper small intestine to 5-methyltetrahydrofolic acid (as happens for all naturally-occurring reduced 1-carbon-substituted folates). This ‘validates’ short-term experimental protocols assessing ‘relative’ folate absorption in human subjects that use folic acid as the ‘reference’ dose. The underlying scientific premise on which this consensus is based is challenged on three grounds: (i) the apparent absence of a 5-methyltetrahydrofolic acid response in the human hepatic portal vein following absorption of folic acid, (ii) the low dihydrofolate reductase activity peculiar to man and (iii) the implications derived from recent stable-isotope studies of folate absorption. It is concluded that the historically accepted case for folic acid being a suitable ‘reference folate’ for studies of the ‘relative absorption’ of reduced folates in human subjects is invalid. It is hypothesised that the liver, and not the absorptive cells of the upper small intestine, is the initial site of folic acid metabolism in man and that this may have important implications for its use as a supplement or fortificant since human liver's low capacity for reduction may eventually give rise to saturation, resulting in significant (and potentially deleterious) unmetabolised folic acid entering the systemic circulation