Bile folate

It was suggested by Hillman (H6) that an enterohepatic cycle has an important role in folate homeostasis. This was based on the observation that alcohol appeared to reduce the level of folate supplied to serum and tissue by interfering with folate clearance into bile. Studies in rats of this aspect of the folate cycle confirm that the enterohepatic pathway has a major role in folate homeostasis. It has been shown that when small amounts of radio-labeled methylpteroylmonoglutamate and pteroylmonoglutamate are placed in the rat jejunum they are both rapidly absorbed and transported to the liver. They are then cleared into the bile predominantly in the methyl form. The original methyl form appears in the bile unchanged 10 min after administration and the pteroylmonoglutamate appears in the bile after conversion to the methyl form in a similar time period. This confirms that only a very short period of time is required for methylation. Bile folate is reabsorbed for... 

Some methods for the determination of added folic acid, and even endogenous 5-CH3-H4-folate, do not use heating for extraction (31-33). For example, in the analysis of bile folates, Shimoda et al. (34) first stored the samples in... 

MRP1 (ABCC1) Glucuronides and sulfate conjugates of steroid hormones and bile salts, colchicine, doxorubicin, daunorubicin, epirubicin, folate, irinotecan, methotrexate, pacitaxel, vinblastine, vincristine, and others... 

The risk of colon cancer appears to be inversely related to calcium and folate intake. Calciums protective effect may be related to a reduction in mucosal cell proliferation rates or through its binding to bile salts in the intestine, whereas dietary folate helps in maintaining normal bowel mucosa. Additional micronutrient deficiencies have been demonstrated through several studies to increase colorectal cancer risk and include selenium, vitamin C, vitamin D, vitamin E, and 3-carotene however, the benefit of dietary supplementation does not appear to be substantial.11... 

Demethylated tetrahydrofolate monoglutamate is released hy extrahepatic tissues and is transported hound to a plasma folate binding protein similar to that in milk. It has a very low affinity for methyl-tetrahydrofolate and other one-carbon substituted derivatives. It functions mainly to return folate to the liver, where it is either conjugated for storage or methylated to 5-methyl-tetrahydrofolate that is secreted in the bile. 

There is considerable enterohepatic circulation of folate, equivcdent to about one-third of the dietary inttike. Methyl-tetrahydrofolate is secreted in the bile, then reabsorbed in the jejunum together with food folates. In experimented animeds, bile drainage for 6 hours results in a reduction of serum folate to 30% to 40% of normal (Steinberg et ed., 1979). There is very little loss of folate jejunal absorption is very efficient, emd the fecal excretion of 450 nmol (200 of folates per day largely represents synthesis by intestinal flora and does not reflect inttike to any significant extent. 

L-Tyrosine metabolism and catecholamine biosynthesis occur laigely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andUpid metabolism. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bile acids and the detoxification process of aromatic drugs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabolism related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

In rats, OAT-K2, as OAT-Kl, was localized in the apical membrane of straight proximal tubule [52]. When transfected in cultured epithehal cells, it mediates not only the apical transport of methotrexate and folate but also that of taurocholate and prostaglandin E2. In cis-inhibition studies, steroids, bile acid analogs, and cardiac glycosides were shown to have a high affinity for OAT-K2, suggesting that it participates to the apical transport of hydrophobic anionic compounds in the kidney [52]. 

Decreases fecal bile acids reduces consumption of heterocyclic amines and other carcinogens that are produced through meat preparation and processing techniques Inhibit COX-2 induce apoptosis via 15-10X-1 Increases levels of intracellular folate... 

Cerebrospinal fluid contains a folate binder which appears identical to that present in serum except that it is unsaturated. Similar binders have been found in bile and urine but have not been well characterized (C6). 

Impaired absorption has been found in some patients with malignant disease, but this is probably related to active disease close to or actually involving the small intestine (P3, K9). Little information is available on folate metabolism in patients with hepatic carcinoma and its effect on the recycling of folate in bile. 

The hver, which stores half of the body s folate, takes up much of the folate from the portal circulation uptake may be through active transport or receptor-mediated endocy-tosis. Within the liver, FH4 is reconjugated to the polyglutamate form before being used in reactions. A small amount of the folate is partially degraded, and the components enter the urine. A relatively large portion of the folate enters the bile and is subsequently reabsorbed (very similar to the fate of bile salts in the enterohepatic circulation). 

Folic acid is essential for body growth and is needed to synthesize DNA. Folic acid is found in leafy green vegetables, yellow fruits and vegetables, yeast, and meat and is absorbed in the small intestine. The active form of folic acid—called folate—circulates to all tissues in the body. A third of folate is stored in the liver and the remainder is stored in other tissues. Most folic acid is excreted in bile... 

Some recent studies on vitamin transport using membrane vesicles include those of vitamin B6 by rat kidney brush border membranes (Bowman et al, 1990), ascorbic acid by teleost intestinal brush border membranes (Mafha et ai, 1993), biotin by human kidney brush border membranes (Baur and Baumgartner, 1992), pantothenate by human placental brush border membranes (Grassl, 1992), folate and riboflavin by rabbit intestinal brush border membranes (Said and Mohammadkhani, 1993a,b Said et al, 1993), and thiamine by rat small intestine basolateral membranes (Laforenza et al, 1993). Bile acid transport in human placental, rat ileal, and rabbit small intestinal brush border membrane vesicles (Dumaswala et al, 1993 Gong et al, 1991 Kramer et al, 1993) and the effect of vitamin D status... 

The pathophysiology and clinical setting of the blind-loop syndrome have been reviewed recently by Donaldson (30). It is clear that a resident bacterial flora in the proximal small intestine has a major role in the development of the absorptive and luminal defects which have been observed repeatedly in these patients (20,31-35), who have a variety of basic illness, and in experimental animals (31,36) in which an antiperistaltic pouch has been constructed either in the proximal or middle jejunum. However, the presence and extent of the absorptive defects, i.e., vitamin B12, folate, xylose, and lipid, as well as the extent of luminal metabolic alteration of bile salts have varied in individual patients. This variability is probably related to... 

The liver rapidly absorbs from 10 to 20% of dietary folate, with a preference for non-methylated and non-reduced derivatives, while peripheral tissues are enriched in reduced and methylated functional derivatives. Folate is mainly stored in the liver. Hepatic folates are partly excreted into the bile enterohepatic circulation and reabsorbed (Steinberg et al. 1979). This is one of the mechanisms involved in the recirculation of folate. Regarding renal elimination, folate is filtered by the glomerulus and reabsorbed into the proximal tubule. The daily urinary excretion of intact folates is between 1 to 12 pg. When the serum plasma folate concentration is very high, it is possible to overwhelm the renal reabsorption capacity in this case, folate derivatives are excreted in the urine. Due to the possible production by the gut microflora, fecal folate levels are quite high. 

About 80% of dietary folate is in the form of polyglutamates a variable amount may be replaced by various one-carbon fragments or be present as dihydrofolate derivatives. Folate conjugates are hydrolysed in the small intestine by conjugase (pteroyl-polyglutamate hydrolase), a zinc-dependent enzyme of the pancreatic juice, bile and mucosal brush border zinc deficiency can impair folate absorption. Free folate, released by conjugase action, is absorbed by active transport in the jejunum. 

---