Intestinal Absorption Of Folic Acid Research Articles

Functional characterization of folic acid transport in the intestine of the laying hen using the everted intestinal sac model

Absorption at the level of the intestine is likely a primary regulatory mechanism for the deposition of dietary supplemented folic acid into the chicken egg. Therefore, factors affecting the intestinal transport of folic acid in the laying hen may influence the level of egg folate concentrations. To this end, a series of experiments using intestinal everted sacs were conducted to characterize intestinal folic acid absorption processes in laying hens. Effects of naturally occurring folate derivatives (5-methyl and 10-formyltetrahydrofolate) as well as heme on folic acid absorption were also investigated. Folic acid absorption was measured based on the rate of uptake of (3)H-labeled folic acid in the everted sac from various segments of the small and large intestines. Folic acid concentration, incubation length, and pH condition were optimized before the performance of uptake experiments. The distribution profile of folic acid transport along the intestine was highest in the upper half of the small intestine. Maximum uptake rate (nmol·100 g tissue(-1)·min(-1)) was observed in the duodenum (20.6 ± 1.9) and jejunum (22.3 ± 2.0) and decreased significantly in the ileum (15.3 ± 1.1) and cecum (9.3 ± 0.9). Transport increased proportionately (P < 0.05) between 0.0001 and 0.1 µM folic acid. Above 0.1 µM, the slope of the regression line was not significantly different from zero (P < 0.137). Folic acid uptake in the jejunum showed a maximum rate of transport at pH 6.0, but was lowest at pH 7.5. The presence of 5-methyl and 10-formyltetrahydrofolate as well as heme impeded folic acid uptake, reducing intestinal folic acid absorption when added at concentrations ranging from 0 to 100 µM. Overall, these data indicated the presence of a folic acid transport system in the entire intestine of the laying hen. Uptake of folic acid in the cecum raises the likelihood of absorption of bacterial-derived folate.

Regulatory mechanisms of intestinal folate uptake in a rat model of folate oversupplementation

Folic acid is essential for numerous biological functions, ranging from nucleotide biosynthesis to the remethylation of homocysteine. Folic acid is unable to cross the biological membranes by simple diffusion, so there exists a well-developed epithelial folate transport system for the regulation of normal folate homeostasis in the intestine. Any perturbances in the folate uptake system might lead to a state of folate deficiency, which in turn is strongly associated with the risk of various cancers, birth defects and CVD. Countries with obligatory folate fortification of food (USA and Canada) have documented a significant decrease in neural tube defects in newborns. However, the effect of folate oversupplementation on the intestinal absorption of folic acid has not been studied. We studied the process of folate transport and the expression of folate transporters in the rat intestine after folate oversupplementation. Rats were oversupplemented with tenfold the normal requirement of folic acid for periods of 10 and 60 d. Folate uptake in intestinal brush-border membrane vesicles followed saturable kinetics with pH optimum at 5·5. Acute, but not chronic, folate oversupplementation led to a significant down-regulation in intestinal folate uptake at acidic pH optima and was associated with a decrease in Vmax without any significant change in the Km of the folate uptake process. The decrease in folate uptake was also associated with the down-regulation in the protein levels of major folate transporters, proton-coupled folate transporter (PCFT) and reduced folate carrier (RFC), without altering their mRNA levels. Hence, it was concluded that acute folate oversupplementation results in a significant decrease in intestinal folate uptake by down-regulating the expressions of RFC and PCFT, via some post-transcriptional or translational mechanisms.

Inhibition of Folic Acid Uptake by Catechins and Tea Extracts in Caco-2 Cells

In this present study it was aimed to determine whether the catechins contained in green tea and the whole extracts of Camellia sinensis (Theaceae) inhibit the uptake of folic acid by Caco-2 cell monolayers. Our results indicate that (-)-epigallocatechin 3-gallate (EGCG) and (-)-epicatechin 3-gallate (ECG) inhibit cellular folic acid uptake with IC50 values of 34.8 micromol/L and 30.8 micromol/L, respectively. Furthermore, green and black tea extracts were also found to inhibit folic acid uptake with IC50 values of approximately 7.5 and 3.6 mg/mL, respectively. According to these results, simultaneous intake of tea and folic acid may inhibit intestinal folic acid absorption. The consequences with respect to the folate status of the body will need to be examined in vivo.

Effects of maternal ethanol consumption during pregnancy or lactation on intestinal absorption of folic acid in suckling rats

A fostering/crossfostering analysis of the effects of maternal ethanol exposure on jejunal and ileal folate absorption was performed. Male and female rats were randomized into two groups. In the first group, ethanol-treated rats received ad libitum 5, 10 and 15% ethanol in the drinking fluid during three successive weeks. A consumption of 20% was maintained in this group for 5 additional weeks. Ethanol-treated rats were mated. Group 2 served as the control. To study the effect of chronic alcoholism during lactation or gestation separately, at birth (2nd day postpartum) control new-borns were cross-fostered to ethanol dams (EG), and the pups issued from the ethanol treated mothers were cross-fostered to control dams (CG). Thus, three experimental groups of pups were formed: (1) control pups receiving no treatment during gestation and lactation (CG); (2) pups exposed to ethanol only during gestation (GG); and (3) pups exposed to ethanol only during lactation (LG). At 21 days postpartum the jejunal and distal ileum folate absorption was determined in the offspring rats by a perfusion technique. Milk folic acid levels were determined by an immunoluminometric assay. The results showed an increase in jejunal folic acid absorption in offsprings exposed to ethanol only during the lactation period (LG). However, in pups exposed to ethanol only during the gestation period (GG), the jejunal folic acid absorption was significantly increased only at concentrations of 0.25, 0.5 and 2.5 μM. No free folic acid absorption occurred in the distal ileum of control pups (CG) at day 21 at all assayed concentrations but in offsprings exposed to ethanol only during the gestation or lactation periods absorption did take place. Pups exposed to ethanol during the gestation period (GG) showed decreased values in ileum folic acid absorption at the lowest assayed concentration (0.25 μM) compared to values obtained for pups exposed to ethanol only during lactation (LG). Milk folic acid levels were significantly decreased in the ethanol-fed dams on day 21 of lactation. These results indicate that exposure of rats to ethanol during the lactation period affects more severely postnatal development of intestinal functions than ethanol exposure only during gestation. In summary, both the exposure to ethanol itself and the decrease in folic acid intake caused alterations in the function of the intestinal mucosa in the offspring, which in turn altered absorption time and development. However, the present results do not explain how ethanol stimulated intestinal absorption of folic acid in pups exposed to ethanol during the gestation or lactation periods. Further studies are needed.

Metabolic Interactions of Alcohol and Folate

The goals and objectives of these studies, conducted over the past 30 y, were to determine: a) how chronic alcoholism leads to folate deficiency and b) how folate deficiency contributes to the pathogenesis of alcoholic liver disease (ALD). The intestinal absorption of folic acid was decreased in binge drinking alcoholics and, prospectively, in volunteers fed alcohol with low folate diets. Monkeys fed alcohol for 2 y developed decreased hepatic folate stores, folic acid malabsorption and decreased hepatic uptake but increased urinary excretion of labeled folic acid. Micropigs fed alcohol for 1 y developed features of ALD in association with decreased translation and activity of intestinal reduced folate carrier. Another study in ethanol-fed micropigs demonstrated abnormal hepatic methionine and DNA nucleotide imbalance and increased hepatocellular apoptosis. When alcohol feeding was combined with folate deficiency, micropigs developed typical histological features of ALD in 14 wk, together with elevated plasma homocysteine levels, reduced liver S-adenosylmethionine and glutathione and increased markers for DNA and lipid oxidation. In summary, chronic alcohol exposure impairs folate absorption by inhibiting expression of the reduced folate carrier and decreasing the hepatic uptake and renal conservation of circulating folate. At the same time, folate deficiency accelerates alcohol-induced changes in hepatic methionine metabolism while promoting enhanced oxidative liver injury and the histopathology of ALD.

Reduced Folate Carrier: Tissue Distribution and Effects of Chronic Ethanol Intake in the Micropig

Folate deficiency is common in alcoholic patients, in part due to abnormal transport across membranes relevant to folate homeostasis. The reduced folate carrier (RFC) transports monoglutamyl folates across tissue membranes and could be affected by chronic exposure to ethanol. The micropig model is suitable to study the effect of alcoholism on RFC and folate transport across membranes. The membrane transport of [3H]-folic acid was measured by a vacuum filtration method in jejunal brush border (JBB), liver plasma membrane (LPM), and kidney brush border (KBB) membranes vesicles from micropigs fed control or 40% ethanol diets for 12 months. RFC transcripts were analyzed by reverse transcription polymerase chain reaction in jejunal mucosa, liver, and kidney from the same animals. When we compared results from three relevant membranes in control animals, the transport of [3H]-folic acid was highest in LPM, 3-fold lower in KBB (p < 0.001), and 6-fold lower in JBB (p < 0.001). The concentration of RFC transcripts per total RNA was greatest in liver, followed by kidney and jejunum. The transport of [3H]-folic acid by JBB vesicles from chronic ethanol-fed animals exhibited 2-fold lower Km and Vmax (p < 0.05), whereas there was no ethanol effect on the Vmax of [3H]-folic acid transport by LPM or KBB. RFC transcript levels were 10-fold lower in jejunal mucosa from ethanol-fed animals than in control-fed animals (p < 0.005). Although our findings demonstrate different RFC transcript amounts and transport efficiencies among tissues, the present studies suggest that chronic ethanol exposure decreases the intestinal absorption of folic acid by altering the expression of RFC and consequently its transport kinetics in JBB. These findings provide a mechanism for the clinical finding of reduced folic acid absorption in chronic alcoholics.

Intestinal Absorption and Enterohepatic Circulation of Folic Acid: Effect of Ethanol

This study sought to determine the intestinal in vivo absorption of folic acid by the whole intestine, and the appearance of this compound in bile in control and ethanol-fed rats. Intestinal folic acid absorption in rats with the bile duct cannulated decreased in ethanol-fed rats with respect to control rats. This difference was significant at 1 and 2.5 µM concentrations of folic acid. This result is in contrast with previous work in our laboratory on rats with intact bile ducts, where ethanol-fed rats had an increase in folic acid absorption. The results obtained in the present work suggest an impaired enterohepatic recycling of folic acid in ethanol-fed rats.

Comparative Effects of Intestinal Absorption of Folic Acid and Methyltetrahydrofolic Acid in Chronic Ethanol-Fed-Rats

This study concerns in vivo folic acid and methyltetrahydrofolic acid (MTHF) absorption by the whole intestinal surface after 20 weeks of 30% ethanol ingestion in drinking water. The results were compared with control rats fed ad libitum. The total intestinal serosal areas were similar in ethanol-fed and control rats. Significant increases in intestinal length, and decreases in tissue wet and dry weights were found in ethanol-fed rats. Serum folic acid concentrations were significantly less in the animals which had ingested ethanol than in the control rats. Intestinal folic acid absorption was significantly increased at lower substrate concentrations (0.5 and 1 microM), while no difference was observed at 2.5 microM in the ethanol-fed rats. Folic acid absorption relative to tissue wet weight showed significant increases at all tested concentrations in the ethanol-fed rats. Intestinal MTHF absorption showed no significant changes at 0.5 microM MTHF concentration, and an increase was observed in the absorption values at 1 and 2.5 microM concentrations in the ethanol-fed rats. When expressed as tissue wet weight, MTHF absorption values in ethanol-fed rats increased at 1 and 2.5 microM but did not differ at 0.5 microM substrate concentrations. The above results indicate compensatory responses in the folic acid and MTHF intestinal absorption after chronic ethanol ingestion. These effects are observed when the whole intestinal surface is evaluated.

Intestinal folic acid absorption and the acid microclimate. The effects of compounds relevant to folate malabsorption.

The effect s of various substances and circumstances on folic acid absorption and surface pH were investigated in vitro in rat proximal jejunum. Prior consumption of alcohol and libitum, phenytoin and in vitro methotrexate had no effect on folate absorption. In contrast, ethanol in vitro, low sodium ion containing buffers in vitro and oral methotrexate given prior to experiment reduced absorption. Folate absorption did not correlate with water movement since methotrexate decreased folate but enhanced fluid absorption, ruling out direct coupling. Surface pH was elevated by the low sodium ion containing buffers, ethanol in vitro and oral methotrexate, correlating inversely with folate absorption. The parallelisms between absorption and changes in surface pH support the microclimate hypothesis of folic acid absorption where the rate of transport is largely determined by the surface pH of the proximal jejunum.

Folate content of Iranian breads and the effect of their fiber content on the intestinal absorption of folic acid

Folate deficiency is a relatively uncommon disorder in central Iran. In order to explain this finding; the acid content of various Iranian breads was determined, since bread is the staple food in Iran. Tanok, the village wholemeal bread, has an average "free" folate content (without conjugase incubation) of 0.34 mug/g. Sangask and Bazari, leavened breads made from flours of high extraction rates and widely consumed in towns and cities, have aberage "free" folate contents of 0.38 and 0.71 mug/g, respectively. The folate content of these breads are significantly higher than that of white bread from refined flour (0.13 mug/g) or oatmeal bread (0.09 mug/g). Iranian breads also have a high content of indigestible fiber (1.6 to 4.2% of dry weight). Since substances within the bread, such as fiber, may interfere with folate absorption by the small intestine, sequential folate absorption tests (tritiated pterolymonoglutamic acid) were performed in four subjects with meals of increasing fiber content and fasting. No interference with folate absorption was found. Furthermore, in vitro studies did not demonstrate the formation of insoluble complexes between bread fiber and folic acid, which might indicate decreased availability.

Folic acid absorption in regional enteritis

The authors have investigated intestinal absorption of folic acid by jejunal perfusion with a triple lumen tube in five subjects with regional enteritis. The subjects' intestinal disabilities ranged from terminal ileitis to short bowel syndrome. Two had steatorrhea and two had low serum folate levels. Absorption of pteroylglutamic acid was normal in all five. This suggests that folic acid deficiency, common in this disorder, is largely caused by malnutrition, not malabsorption.

A Modified Fecal Excretion Test for Assaying Intestinal Absorption of 3H-Folic Acid

A method for determination of the intestinal absorption of folic acid is described. It is based on the principle of double tracer technique in assay of fecal samples using gas proportional counting for 3H determinations. As the procedure is simple, reliable, and inexpensive, it is considered to be of value for laboratories without advanced equipment for radiochemical assay.

Inhibition of Intestinal Absorption of Folic Acid by Phenytoin

Folate deficiency in four patients could be ascribed to anticonvulsant therapy with phenytoin. Their intestinal absorption of folic acid was depressed only when phenytoin was given simultaneously. Otherwise the absorption of folic acid was normal. This malabsorption of folic acid is probably due to a rise in the jejunal pH produced by phenytoin. It is assumed, however, that this effect of phenytoin is rather the result than the cause of folate deficiency occurring during anticonvulsant drug therapy.

Drugs, toxins and dietary amino acids affecting vitamin B 12 or folic acid absorption or utilization

Absorption, transport or utilization of vitamin B 12 or folic acid is reduced by a growing number of drugs, as well as by ethanol and certain dietary amino acids. In most cases this results in only slight vitamin B 12 or folic acid deficiency, but overt megaloblastic anemia may occur when drug dose is high and prolonged, and particularly when associated with pre-treatment borderline or decreased vitamin stores. Patients treated for protracted periods with anticonvulsants frequently have borderline folate stores, perhaps related both to poor diet and anticonvulsant-induced malabsorption. Oral contraceptive agents have been reported to be associated with folic acid deficiency and megaloblastic anemia. Folic acid antagonists (FAA) include agents for cancer chemotherapy, immunosuppression, psoriasis, protozoacides and antibacterials. Comparison of short-term cultures of human bone marrow with similar cultures of pathogenic microorganisms or neoplastic cells can measure the relative effects of new or suspected FAA on folate-dependent steps in DNA synthesis in vitro and may make it possible to predict use in vivo. Vitamin B 12 antagonists are just beginning to be studied in this way. Various drugs reduce intestinal absorption of folic acid or vitamin B 12. Ethanol may interfere with folic acid and B 12 metabolism by a variety of mechanisms, including production of intestinal malabsorption and interference with folate metabolism, and possibly may act as a hematologic toxin by mechanisms other than disturbance of vitamin B 12 or folic acid metabolism. Methionine, homocysteine, serine and glycine are involved in the biochemical cycle whereby folate coenzymes interconvert; vitamin B 12 and pyridoxine are also involved in this cycle, and thus all these agents indirectly function in DNA-thymine synthesis. Homocystinuria and hyperglycinemia are associated with hematologic abnormalities which may relate to disturbed vitamin B 12 and folic acid metabolism. Vitamin B 12 deficient megaloblastosis may be provoked or aggravated by methionine.

Metabolic studies of folic acid in non-malignant diseases.

Abstract. The effect upon the serum folic acid activity (SFAA) of age, acute illness and chronic illness has been studied in 173 persons. Old, healthy subjects getting proper meals from institutional kitchens have normal SFAA, while those preparing their own food have low SFAA. The SFAA is normal in acute illness (thyreotoxicosis, fractures, after operations). In chronic inflammatory diseases (pulmonary tuberculosis, rheumatoid arthritis) low or subnormal SFAA is common. In rheumatoid arthritis patients the SFAA is lower the more active the disease and the higher the erythrocyte sedimentation rate. Serum iron and serum cholesterol are also low and correlated to both SFAA and sedimentation rate. The intestinal absorption of folic acid is normal in patients with rheumatoid arthritis, while the plasma clearance of folic acid is greatly increased. The high frequency of subnormal SFAA in this group may be explained by inadequate diet and/or increased turnover of folic acid in the plasma.

Intestinal absorption of folic acid using h3-labelled folic acid

Intestinal absorption of folic acid using h3-labelled folic acid