Bioavailability and bioefficacy of folate and folic acid in man.

Folic acid is important because supplementation around the time of conception has been proven to lower the risk of having offspring with a neural-tube defect. Furthermore, both dietary folate and folic acid decrease plasma total homocysteine concentrations. Elevated plasma homocysteine concentrations are considered to be an independent risk factor for cardiovascular disease. The aim of the present review is to give an overview of factors influencing bioavailability and bioefficacy (the proportion of ingested nutrient converted to its active form) of food folate and folic acid, and to discuss the functional bioefficacy of folate and folic acid in decreasing plasma homocysteine concentrations. We use the mnemonic SLAMENGHI to group factors influencing bioavailability and bioefficacy: Species of folate; Linkage at molecular level; Amount of folate and folic acid consumed; Matrix; Effect modifiers; Nutrient status; Genetic factors; Host-related factors; mathematical Interactions between the various factors. Bioefficacy of folate from some foods is 50 % that of folic acid. This factor is most probably explained by the matrix factors, encapsulation and binding. However, often such effects cannot be distinguished from factors such as species, chain length of folate in food, effect modifiers and the amount of folate consumed in a meal. Folic acid provided as a supplement is well absorbed. However, the homocysteine-lowering capacity of doses of folic acid >500 mug is limited. It is unclear whether unmetabolised folic acid poses health risks. This factor is of importance, because food fortification is now implemented in many countries and folic acid supplements are freely available. In particular circumstances host-related factors, such as gastrointestinal illness and pH of the jejunum, can influence bioavailability. Genetic factors also deserve attention for future research, because polymorphisms may influence folate bioavailability.

Bioavailability of folate from processed spinach in humans. Effect of food matrix and interaction with carotenoids.

The effect of the food matrix and dietary fibre on the bioavailability of folate is not known. In a controlled, 3-week dietary intervention study, 28 men and 42 women were divided into six groups to receive either a control diet (n = 10), or the control diet plus 20 g/MJ per day (n = 12 per group) of whole-leaf spinach, minced spinach, liquefied spinach, or liquefied spinach to which dietary fibre (10 g/kg wet weight) was added. The sixth group received the control diet plus a synthetic carotenoid supplement with similar amounts of beta-carotene and lutein as found in spinach. A significantly higher plasma folate response was found for the pooled spinach groups than for the control group. Among the spinach groups no significant differences were detected. However, the plasma folate response of the pooled minced and liquefied spinach groups was greater than that of the whole-leaf spinach group (p = 0.03). Re-addition of dietary fibre to the liquefied spinach to compensate for the fibre broken down during liquefaction did not reduce the plasma folate response. The consumption of the carotenoid supplement did not have an effect on plasma folate concentrations compared with the control group. The food matrix in which the folate is entrapped plays a role in folate bioavailability.

Homocysteine metabolism and effects of folic acid supplementation in patients affected with spina bifida.

Folic acid supplementation around conception decreases the risk of having offspring with a neural tube defect. However, the aetiology is often still unknown. This study investigated whether spina bifida patients have lower blood folate and higher fasting and post-methionine-load plasma total homocysteine (tHcy) concentrations than control patients. Moreover, the effects of supplementation with 500 microg folic acid/d on folate and tHcy concentrations were determined. Spina bifida patients (n = 12) and disabled control patients (n = 15) received 4 weeks of placebo treatment followed by 4 weeks of intervention with 500 microg folic acid/d. Blood was collected at the start and after 4 and 8 weeks. A methionine-loading test was performed at the start and the end of the study. At baseline, no significant differences occurred between spina bifida and control patients. Folic acid supplementation significantly increased plasma and red blood cell folate concentrations in both groups. Folic acid decreased fasting tHcy concentrations in control patients by 1.6+/-0.5 micromol/l (p<0.01) and in spina bifida patients by 2.2 +/- 1.3 micromol/l (p = 0.10). This study does not show a derangement in homocysteine metabolism in spina bifida compared to control patients. Moreover, folic acid supplementation seems at least as effective in spina bifida patients as in controls.

Homocysteine-lowering effect of 500 microg folic acid every other day versus 250 microg/day.

BACKGROUND/AIMS: Elevated plasma total homocysteine (tHcy) concentrations are a risk factor for neural tube defects and vascular diseases. Supplementation with folic acid decreases tHcy. We investigated whether supplementation with 500 microg folic acid every other day is as effective in lowering tHcy as 250 microg folic acid each day. METHODS: In a 4-week intervention study, 22 healthy young women (18-40 years old) took either 500 microg folic acid every other day (500-microg/2d group) or 250 microg folic acid each day (250-microg/d group). Fasting blood was collected on days 0 and 28. RESULTS: Plasma folate concentrations increased by 11.4 nmol/l (6.8-15.9) in the 250-microg/d group and by 9.1 nmol/l (95% CI 1.9-16.3) in the 500-microg/2d group. These increases were not significantly different from each other. THcy concentrations decreased by 1.52 micromol/l (95% CI -2.09 to -0.95; p < 0.001) in the 250-microg/d group and by 0.88 micromol/l (-1.53 to -0.23; p < 0.05) in the 500-microg/2d group. The difference in decrease between the 250-microg/d group and the 500-microg/2d group was 0.64 micromol/l (p = 0.11). CONCLUSION: Although not conclusive, this study suggests that supplying subjects with folic acid each day decreases tHcy more effectively than a double dose every other day.

Low-Dose folic acid supplementation decreases plasma homocysteine concentrations: a randomised trial.

An elevated plasma total homocysteine concentration is a risk factor for cardiovascular disease and neural tube defects. A high daily intake of supplemental folic acid is known to decrease total homocysteine concentrations. We studied the effect of low-dose folic acid administration (250 or 500 microg/day for 4 weeks on plasma total homocysteine concentrations and folate status. We also investigated whether total homocysteine concentrations and blood folate concentrations returned to baseline after an 8-week washout period. In this placebo-controlled study, 144 healthy women aged 18-40 years received 500 microg folic acid per day, 500 microg folic acid every second day (250 microg/day), or a placebo tablet with their habitual diet (mean dietary folate intake 280 microg/day). Administration of 250 and 500 microg folic acid per day for four weeks significantly increased folate concentrations in plasma (p<0.001) and red blood cells (p<0.01). Total homocysteine concentrations decreased significantly (p<0.001) in women (n=50) who took 250 microg folic acid daily [mean (+/- SEM) deviation from baseline -11.4 +/-1.98%] and in women (n=45) who took 500 microg folic acid daily (-21.8 +/- 1.49%). Eight weeks after the end of the intervention period (week 12), plasma total homocysteine concentrations in the folic acid-supplemented groups had not returned to baseline (week 0). In conclusion, doses of folic acid as low as 250 microg daily, on an average, in addition to usual dietary intakes of folate, significantly decreased plasma total homocysteine concentrations in healthy, young women. An 8-week washout period was not sufficient for blood folate and plasma total homocysteine concentrations to return to baseline concentration

Bioavailability of lutein from vegetables is 5 times higher than that of beta-carotene.

BACKGROUND: To gain more insight into the relation between vegetable consumption and the risk of chronic diseases, it is important to determine the bioavailability of carotenoids from vegetables and the effect of vegetable consumption on selected biomarkers of chronic diseases. OBJECTIVE: To assess the bioavailability of beta-carotene and lutein from vegetables and the effect of increased vegetable consumption on the ex vivo oxidizability of LDL. DESIGN: Over 4 wk, 22 healthy adult subjects consumed a high-vegetable diet (490 g/d), 22 consumed a low-vegetable diet (130 g/d), and 10 consumed a low-vegetable diet supplemented with pure beta-carotene (6 mg/d) and lutein (9 mg/d). RESULTS: Plasma concentrations of vitamin C and carotenoids (ie, alpha-carotene, beta-carotene, lutein, zeaxanthin, and beta-cryptoxanthin) were significantly higher after the high-vegetable diet than after the low-vegetable diet. In addition to an increase in plasma beta-carotene and lutein, the pure carotenoid-supplemented diet induced a significant decrease in plasma lycopene concentration of -0.11 micromol/L (95% CI: -0.21, -0.0061). The responses of plasma beta-carotene and lutein to the high-vegetable diet were 14% and 67%, respectively, of those to the pure carotenoid- supplemented diet. Conversion of beta-carotene to retinol may have attenuated its plasma response compared with that of lutein. There was no significant effect on the resistance of LDL to oxidation ex vivo. CONCLUSIONS: Increased vegetable consumption enhances plasma vitamin C and carotenoid concentrations, but not resistance of LDL to oxidation. The relative bioavailability of lutein from vegetables is higher than that of beta-carotene.

Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trial.

Elevated total plasma homocysteine (tHcy) concentrations are considered a risk factor for neural tube defects (NTD) and cardiovascular disease. Supplementation with folic acid decreases the risk of women having children with NTD. In both sexes, it decreases tHcy levels. We investigated the efficacy of natural dietary folate in improving folate and homocysteine status. We performed a 4-wk dietary controlled, parallel design intervention trial with 66 healthy subjects (18-45 y) divided into 3 treatment groups: the dietary folate group, the folic acid group and the placebo group. Each day each group was fed a different diet. The dietary folate group received a diet high in vegetables and citrus fruit (total folate content approximately 560 microgram) plus a placebo tablet. The folic acid group received a diet naturally low in folate (approximately 210 microgram) plus 500 microgram folic acid and placebo tablet on alternate days, i.e., 250 microgram folic acid/d. And the placebo group received the same low-folate diet as the folic acid group plus a placebo tablet. After 4 wk of intervention, folate status improved, and tHcy concentrations decreased in both the dietary folate and the folic acid groups. From the amount of additional folate (350 microgram/d) and folic acid (250 microgram/d) consumed, the relative bioavailability of dietary folate compared to folic acid was calculated to be 60-98%, depending on the endpoint used. In conclusion, increasing the consumption of vegetables and citrus fruit, both good sources of folate, will improve folate status and decrease tHcy concentrations. This may contribute to the prevention of cardiovascular disease and NTD in the general population

Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial.

BACKGROUND: An elevated plasma total homocysteine concentration is a risk factor for cardiovascular disease and neural tube defects. A high daily intake of supplemental folic acid is known to decrease total homocysteine concentrations. OBJECTIVE: We studied the effect of low-dose folic acid administration (250 or 500 (microgram/d) for 4 wk on plasma total homocysteine concentrations and folate status. We also investigated whether total homocysteine concentrations and blood folate concentrations returned to baseline after an 8-wk washout period. DESIGN: In this placebo-controlled study, 144 healthy women aged 18-40 y received 500 microgram folic acid/d, 500 microgram folic acid every second day (250 microgram/d), or a placebo tablet with their habitual diet (mean dietary folate intake: 280 microgram/d). RESULTS: Administration of 250 and 500 microgram folic acid/d for 4 wk significantly increased folate concentrations in plasma (P < 0.001) and red blood cells (P < 0.01). Total homocysteine concentrations decreased significantly (P < 0.001) in women (n = 50) who took 250 microgram folic acid/d [mean (+/-SEM) deviation from baseline: - 11.4 +/- 198%] and in women (n = 45) who took 500 microgram folic acid/d (-21.8 + 1.49%). Eight weeks after the end of the intervention period (week 12), plasma total homocysteine concentrations in the folic acid-supplemented groups had not returned to baseline (week 0). CONCLUSIONS: Doses of folic acid as low as 250 microgram/d, on average, in addition to usual dietary intakes of folate significantly decreased plasma total homocysteine concentrations in healthy, young women. An 8-wk washout period was not sufficient for blood folate and plasma total homocysteine concentrations to return to baseline concentrations.

Low-dose folic acid supplementation does not influence plasma methionine concentrations in young non-pregnant women.

An elevated plasma total homocysteine (tHcy) concentration is a risk factor for cardiovascular disease and for having offspring with a neural-tube defect. Folate is a methyl donor in the remethylation of homocysteine into methionine. Although folic acid supplementation decreases tHcy concentrations, effects of folic acid supplementation on plasma methionine concentrations are unclear. There is also concern that folic acid supplementation negatively affects vitamin B12 status. We studied effects of low-dose folic acid supplementation on methionine and vitamin B12 concentrations in plasma. We also investigated whether baseline plasma methionine and tHcy concentrations correlated with the baseline folate and vitamin B12 status. For a period of 4 weeks, 144 young women received either 500 micrograms folic acid each day, or 500 micrograms folic acid and placebo tablets on alternate days, or a placebo tablet each day. Plasma methionine, tHcy and plasma vitamin B12 concentrations were measured at start and end of the intervention period. Folic acid supplementation had no effect on plasma methionine or plasma vitamin B12 concentrations although it significantly decreased tHcy concentrations. Plasma methionine concentrations showed no correlation with either tHcy concentrations (Spearman rs-0.01, P = 0.89), or any of the blood vitamin variables at baseline. Baseline tHcy concentrations showed a slight inverse correlation with baseline concentrations of plasma vitamin B12 (rs-0.25, P < 0.001), plasma folate (rs-0.24, P < 0.01) and erythrocyte folate (rs-0.19, P < 0.05). In conclusion, low-dose folic acid supplementation did not influence plasma methionine or plasma vitamin B12 concentrations. Furthermore, no correlation between plasma methionine concentrations and the blood folate and vitamin B12 status was shown.

Folate intake in Europe: recommended, actual and desired intake.

OBJECTIVES: To evaluate possible inconsistencies between recommended, actual and desired folate intake in European adult populations. DESIGN: Review of dietary recommendations, of food consumption surveys, and of intervention and observational studies relating folate intake to the risk of neural tube defects and plasma homocysteine levels. RESULTS: In Europe, mean dietary folate intake in adults is 291 micrograms/d (range 197-326) for men and 247 micrograms/d (range 168-320) for women. The recommended intakes vary between 200-300 micrograms/d (men) and 170-300 micrograms/d (women). However, women with a previous pregnancy affected by a neural tube defect (NTD), are recommended to take 4000 micrograms/d of supplemental folic acid when planning a subsequent pregnancy. For those without a history of NTD, the use of 400 micrograms/d of supplemental folic acid is the best option to prevent the occurrence of NTDs. A daily dose of 650 micrograms supplemental folic acid normalises elevated plasma homocysteine levels, which is a risk factor for cardiovascular diseases. A dietary folate intake of at least 350 micrograms/d is desired to prevent an increase in plasma homocysteine levels of the adult population in general. CONCLUSIONS: Mean dietary folate intake in Europe is in line with recommendations, but the desired dietary intake of > 350 micrograms/d is only reached by a small part of studied European populations. It is considered unethical to investigate whether supplements with a dose lower than 400 micrograms/d of folic acid are also protective against NTDs. However, research to establish the lowest effective dose of dietary folate/supplemental folic acid to optimise homocysteine levels and research on the bioavailability of folate is required. This will enable the choice of a strategy to achieve desired folate intakes in the general population. In the meantime, consumption of plant foods like vegetables, fruits, and cereals should be stimulated to reach the desired level of 350 micrograms of dietary folate per day.

Effects of coffee on cardiovascular responses to stress: a 14-week controlled trial.

We studied the cardiovascular responses to orthostatic and mental stress of 43 healthy subjects who daily received six cups of boiled or filtered coffee and of 21 healthy subjects who abstained from caffeine-containing beverages. All 64 subjects first received six cups of filtered coffee/day for 2 weeks. Then blood pressure (BP) and heart rate (HR) were recorded before, during, and after a "stand upright" test and a mental arithmetic test. Subjects were then randomized to either complete abstinence from caffeine-containing beverages (n = 21), or consumption of six cups of filtered coffee (n = 21), or consumption of six cups of boiled coffee/day (n = 22). The stress tests were repeated after subjects had been on these regimens for 8 weeks. Abstinence from coffee did not affect the responses of BP or HR to orthostatic stress, or the response of BP to mental stress. The increase in HR caused by mental stress was five beats/min less (p = 0.02) in the no-coffee group than in the filtered- (95% confidence interval -8.8 to -1.2) or boiled- (95% confidence interval -8.4 to -0.8) coffee group. It is concluded that elimination of caffeine decreases the HR response to mental stress.

Boiled coffee and blood pressure. A 14-week controlled trial.

The question of whether long-term elimination of coffee from the diet lowers blood pressure has not been settled. Consumption of Scandinavian-style "boiled coffee" is associated with coronary heart disease. However, little is known about the effect of brewing method on the blood pressure-raising potential of coffee. We have studied the effects on blood pressure and heart rate of total elimination of coffee and tea in comparison with drinking boiled coffee consumed as such, or boiled coffee consumed after filtration through paper filter. Thirty-one women and 33 men first consumed 6 cups/day of boiled and filtered coffee for 17 days. Then they were randomly divided into three groups, which for the next 79 days received either unfiltered boiled coffee (caffeine content 860 mg/l), boiled-and-filtered coffee (887 mg caffeine/l), or no coffee, the latter being replaced by fruit juice and mineral water. Total elimination of coffee did not significantly affect blood pressure or heart rate relative to boiled-and-filtered coffee. In subjects who drank boiled coffee, mean ambulant systolic blood pressure rose significantly relative to those who consumed boiled-and-filtered coffee (mean difference +/- SEM, 3.1 +/- 1.1 mm Hg, p = 0.006). This response showed a tendency to be stronger for women (4.5 +/- 1.8 mm Hg) than for men (1.7 +/- 1.2 mm Hg). We conclude that elimination of filtered coffee has no substantial long-term effect on blood pressure, but consumption of unfiltered boiled coffee may cause a slight but significant rise in systolic blood pressure.

Cholesterol-raising factor from boiled coffee does not pass a paper filter.

Previous studies have indicated that consumption of boiled coffee raises total and low density lipoprotein (LDL) cholesterol, whereas drip-filtered coffee does not. We have tested the effect on serum lipids of consumed coffee that was first boiled and then filtered through commercial paper coffee filters. Sixty-four healthy volunteers consumed six cups per day of this boiled and filtered coffee for 17 days. Then, they were randomly divided into three groups, which, for the next 79 days, received either unfiltered boiled coffee (lipid content, 1.0 g/l), boiled and filtered coffee (0.02 g lipid/l), or no coffee. Serum total cholesterol levels rose by 0.42 mmol/l (16 mg/dl; 95% confidence interval [CI], 0.14-0.71), LDL cholesterol levels by 0.41 mmol/l (16 mg/dl; 95% CI, 0.16-0.66), and apolipoprotein B levels by 8.6 mg/dl (95% CI, 3.8-13.4) in those who consumed boiled coffee relative to those who consumed boiled and filtered coffee. Responses of triglycerides, high density lipoprotein cholesterol, and apolipoprotein A-I did not differ significantly among these groups. No significant effects on serum lipid levels were found in the boiled and filtered coffee-consuming group compared with those who drank no coffee. In subjects who drank boiled coffee, serum campesterol level, an indicator of cholesterol absorption, remained constant. The serum lathosterol level, an indicator of cholesterol synthesis, increased by 11% (p less than 0.05), but the lathosterol to cholesterol ratio did not change. We propose that paper filters of the type used for drip-filtered coffee retain the lipid present in boiled coffee and in that way remove the hypercholesterolemic factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of decaffeinated versus regular coffee on serum lipoproteins. A 12-week double-blind trial.

Reports on the association between caffeine intake and serum cholesterol are inconsistent. In 1988, the authors examined the effect of decaffeinated versus regular coffee on serum lipids in 45 healthy volunteers from the general population living in or near Nijmegen, The Netherlands. Twenty-three women and 22 men aged 25-45 years with a habitual intake of 4-6 cups of regular coffee per day participated in a randomized double-blind crossover trial. They received five cups of regular coffee each day for a period of 6 weeks and five cups of decaffeinated coffee for the next 6 weeks, or vice versa. The background diet was kept constant and was low in caffeine. Differences between the effects of decaffeinated and regular coffee on blood lipids were essentially zero; the effect on serum total cholesterol (+/- standard deviation) was 0.01 (+/- 0.36) mmol/liter (0 +/- 14 mg/dl), that on high density lipoprotein cholesterol was 0.01 (+/- 0.11) mmol/liter (0 +/- 4 mg/dl), and that on triglycerides was 0.03 (+/- 0.29) mmol/liter (3 +/- 26 mg/dl). It was concluded that, in healthy adults, replacement of regular coffee by decaffeinated coffee has no effect on serum cholesterol and lipoproteins.

Effect of a lipid-rich fraction from boiled coffee on serum cholesterol.

Scandinavian-style boiled coffee, which raises serum cholesterol, was found to contain more lipid material than drip filter coffee, which does not. Ten volunteers consumed a lipid-enriched fraction from boiled coffee for six weeks: the supplement provided 77 g of water, 1.3 g of lipid, and 1.6 g of other solids per day. Serum cholesterol rose in every subject; the mean rise was 0.74 mmol/l after three weeks (range -0.09 to 1.48 mmol/l) and 1.06 SD 0.37 mmol/l or 23% after six weeks (range 0.48 to 1.52 mmol/l). The increase was mainly due to low-density-lipoprotein cholesterol, which rose by 29%, but very-low-density lipoprotein cholesterol was also raised, as evidenced by a 55% rise in triglycerides. High-density-lipoprotein cholesterol was unchanged. After supplementation had ended, lipid levels returned to baseline. Boiled coffee thus contains a lipid that powerfully raises serum cholesterol.

Effect of decaffeinated versus regular coffee on blood pressure. A 12-week, double-blind trial.

The effect of decaffeinated versus regular coffee on blood pressure and heart rate was investigated. In a randomized double-blind, crossover trial, 45 healthy volunteers (23 women and 22 men, 25-45 years old) with a habitual intake of 4-6 cups coffee/day received 5 cups of regular coffee each day for a period of 6 weeks, and 5 cups of decaffeinated coffee for the next 6 weeks or vice versa. The background diet was kept constant. The total amount of caffeine ingested was 40 mg during the decaffeinated coffee period and 445 mg during the regular coffee period. Use of decaffeinated coffee led to a significant but small decrease in systolic (mean +/- SEM, -1.5 +/- 0.4 mm Hg; p = 0.002) and diastolic (-1.0 +/- 0.4 mm Hg; p = 0.017) ambulant blood pressure and to a small increase in ambulant heart rate (+1.3 +/- 0.6 beats/min; p = 0.031). Individual differences in rate of caffeine metabolism did not explain differences in long-term response of blood pressure to caffeine. We conclude that in normotensive adults replacement of regular by decaffeinated coffee leads to a real but small fall in blood pressure. However, it remains to be established whether a mass switch from regular to decaffeinated coffee would significantly reduce the total incidence of hypertension-related disorders.