Active Transport in the Intestine

There is some small transport activity in the third quarter of the gut, but the major activity resides in distal fourth. Using smaller segments of rat tissue, Dietschy (3) showed a progressive increase in transport activity within the distal 40% of the intestine. Similar localization of activity has been demonstrated with tissue from pigeons, chickens, mice, hamsters, guinea pigs, and monkeys (13) (see Fig. 2). The absence of this activity in the large intestine was demonstrated by Holt (14). 

The high serosal/mucosal concentration ratios demonstrated by the transporting segments do not by themselves constitute sufficient evidence for an active process. However, two alternative interpretations have been excluded. First, the results cannot be attributed to the ion-trapping mechanism whereby a nonpenetrating anion of a diffusible acid will be concentrated in the compartment of higher pW (15). In fact, the final pH differences between the serosal and mucosal fluids operate against such a mechanism (see Table 

A second possibility would have the ion distribute itself between the two compartments in accordance with the transmucosal electrical potential. 

TABLE I. Final pVL Gradients of Serosal and Mucosal Media after 90 min Incubation of Everted Gut Sacs with Taurocholate  

From Lack and Weiner (11). t Initially, the pH was 7.3 in both compartments. 

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Cefadroxyl and cefaclor are beta-lactam antibiotics which show high affinity for the PepTl carrier system, whereas the other two beta-lactams, cephalotin and cef-metazole, are not recognized by PepTl protein and are not actively transported in the intestine. However, as the VolSurf Caco-2 model predicts that all the beta-lactams are nonpenetrating compounds, it is very probable that, as they rely only the diffusion mechanism, cefadroxyl and cefaclor will not cross the cell monolayer. 

Calcium is absorbed from the intestine by facilitated diffusion and active transport. In the former, Ca " moves from the mucosal to the serosal compartments along a concentration gradient. The active transport system requires a cation pump. In both processes, a calcium-binding protein (CaBP) is thought to be required for the transport. Synthesis of CaBP is activated by 1,25-DHCC. In the active transport, release of Ca " from the mucosal cell into... 

Bile salts secreted into the intestine are efficiently reabsorbed (greater than 95 percent) and reused. The mixture of primary and secondary bile acids and bile salts is absorbed primarily in the ileum. They are actively transported from the intestinal mucosal cells into the portal blood, and are efficiently removed by the liver parenchymal cells. [Note Bile acids are hydrophobic and require a carrier in the portal blood. Albumin carries them in a noncovalent complex, just as it transports fatty acids in blood (see p. 179).] The liver converts both primary and secondary bile acids into bile salts by conjugation with glycine or taurine, and secretes them into the bile. The continuous process of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids, and their subsequent return to the liver as a mixture of bile acids and salts is termed the enterohepatic circulation (see Figure 18.11). Between 15 and 30 g of bile salts are secreted from the liver into the duodenum each day, yet only about 0.5 g is lost daily in the feces. Approximately 0.5 g per day is synthesized from cholesterol in the liver to replace the lost bile acids. Bile acid sequestrants, such as cholestyramine,2 bind bile acids in the gut, prevent their reabsorption, and so promote their excretion. They are used in the treatment of hypercholesterolemia because the removal of bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol into that pathway. [Note Dietary fiber also binds bile acids and increases their excretion.]... 

Bile is secreted into the intestine, and more than 95 percent of the bile acids and salts are efficiently reabsorbed. They are actively transported from the intestinal mucosal cells into the portal blood, where they are carried by albumin back to the liver (enterohepatic circulation). In the liver, the primary and secondary bile acids are reconverted to bile salts, and secreted into the bile. 

Dietary thiamin phosphates are hydrolyzed by intestinal phosphatases, and the resultant free thiamin is absorbed by active transport in the duodenum and proximal jejunum, with little absorption in the rest of the small intestine. 

ALP activity is present in most organs of the body and is especially associated with membranes and cell surfaces located in the mucosa of the small intestine and proximal convoluted tubules of the kidney, in bone (osteoblasts), liver, and placenta. Although the precise metabolic function of the enzyme is not yet understood, it appears that ALP is associated with lipid transport in the intestine and with the calcification process in bone. 

There are four major bile acids (see Figures 47-5 to 47-7). Cholic acid and chenodeoxycholic acid, the primary bile acids, are synthesized in the liver. Bacteria metabolize these primary bile acids to the secondary bile acids—deoxy-cholic acid and lithocholic acid, respectively. Bile acids are conjugated in the liver with the amino acids glycine or taurine. This decreases passive absorption in the biliary tree and proximal small intestine, but permits conservation through active transport in the terminal ileum. This combi-... 

After delivery of lipids, bile acids are subsequently reabsorbed in the intestine by two mechanisms active transport in the distal portion of the ileum and nonionic diffusion in the jejunum and colon. 

The largest data set we have found published for quantitative prediction of Fa is the data set treated by Votano and coworkers [27], who used a training set of 417 compounds and a test set of 195 compounds for model development and validation, respectively. The data came from several different sources [26, 30, 31], the PDR [32], and therapeutic drugs [33], and the compounds included were scrutinized to remove substances reported to be actively transported across the intestinal membrane. A true objective validation of this data set, however, cannot be performed, since the authors do not reveal the compounds included in the study. However, the authors state that a... 

In spite of the obstacles to oral delivery, substantial evidence suggests that pharmaceutical polypeptides are absorbed through the intestinal mucosa, although in minute amounts.10 Small amounts of polypeptide drugs can be absorbed by the action of specific peptide transporters in the intestinal mucosa cells.11 This suggests that properly formulated proteins or peptide drugs may be administered by the oral route with retention of sufficient biological activity for their therapeutic use. 

Riboflavin Uptake and Chemistry (Fig. 8.28). Most dietary riboflavin is eaten as the FAD or FMN coenzymes. Intestinal pyrophosphatases and phosphatases produce free riboflavin, which is actively transported in the proximal area of the small intestine into systemic circulation. Because of its poor water solubility, it is transported on albumin and immunoglobulin proteins. Conversion to the coenzyme forms occurs inside the cells that need these coenzymes. 

Calcium ions are mostly present in bones or chelated to biological molecules. In blood plasma, only 1% of the calcium ions present are unbound 78% is bound to albumin, 8% to citrate, and 13% to other plasma proteins. The free calcium ions are prevented from precipitating by plasma pyrophosphate. Calcium ions are also stored in the endoplasmic reticulum (ER), mostly chelated to ER-resident proteins and phosphatidylser-ine. Free calcium ions may be released through transient receptor potential channels to the cytosol where it activates numerous physiological processes. If the free calcium ion concentration of blood plasma falls, parathyroid hormone (PTH) is secreted by the parathyroid gland cells. PTH speeds up the transport of demineralized bone products by osteoclasts. In the kidney, it increases the excretion of phosphate and decreases the excretion of calcium. PTH also acts on kidney cells to make calcitriol from vitamin D, which induces calcium transporters in the intestine and osteoclasts. PTH mediates these effects by activating G-protein-coupled receptors in the kidney and osteoclasts. 

CFTR discovered 20 years ago, is a cAMP-activated chloride channel, acting as an ATP-dependent pump with ATPase activity, expressed in epithelia in the lung, intestine, pancreas and other tissues, where it facilitates tran-sepithelial fluid transport. In the intestine, CFTR provides the major route for chloride secretion in certain diarrheas. Mutations in CFTR cause the hereditary disease cystic fibrosis, where chronic lung infection and deterioration in lung function cause early death. 

B. Phosphate ion binds the active site on calcium transporters in the intestine, inhibiting their ability to transport calcium. 

Fructose is found in many plants and is an important portion of dietary carbohydrate. Most commonly it is ingested as free fructose or sucrose. Fructose is not actively transported by the intestinal mucosa, and variable proportions are converted to glucose in the process of absorption in man, about one-sixth is converted (Ml). Most of the metabolism of fructose occurs in the liver. If a renal threshold for fructose exists, it is very low. 

Amino acids, dipeptides, and some tripeptides are transported from the lumen of the small intestine through the membrane of the absorptive cells of the brash border, where the peptides are hydrolyzed to amino acids. Transport of peptides and amino acids is active and analogous to glucose transport in the intestine i.e., they are transported by specific protein carriers, together with Na across the cell membrane and they are called sodium symporters. 

In 1958, Riklis and Quastel [104] observed that sodium ion is necessary for sugar transport in the intestine. This finding was confirmed not only in intestine but also in kidney and other cells. Moreover, ouabain, an inhibitor of sodium transport, blocks sugar concentration by epithelial cells. On the other hand, sodium and water absorption is increased in rat intestine when sugar is actively transported. 

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. 

The amormt of absorbed riboflavin that can remain within the body and the circulation (in blood plasma) is strictly regulated by glomerular and tubular filtration and tubular reabsorption in the kidneys. The latter is an active, saturable, sodium-dependent transport process, with characteristics similar to those of active transport in the gastrointestinal tract. It is responsible for the very sharp and characteristic transition between minimal urinary excretion of riboflavin at low intakes, and a much higher level of excretion, proportional to intake, at higher intakes. This transition point has been extensively used to define and to measure riboflavin status and requirements (see below), and to permit studies of intestinal absorption in vivo (see above). Excretion of riboflavin is affected by some chemicals (such as boric acid, which complexes with it), and by certain diseases and hormone imbalances. 

In humans, thiamine is both actively and passively absorbed to a limited level in the intestines, is transported as the free vitamin, is then taken up in actively metabolizing tissues, and is converted to the phosphate esters via ubiquitous thiamine kinases. During thiamine deficiency all tissues stores are readily mobilhed. Because depletion of thiamine levels in erythrocytes parallels that of other tissues, erythrocyte thiamine levels ate used to quantitate severity of the deficiency. As deficiency progresses, thiamine becomes indetectable in the urine, the primary excretory route for this vitamin and its metaboHtes. Six major metaboHtes, of more than 20 total, have been characterized from human urine, including thiamine fragments (7,8), and the corresponding carboxyHc acids (1,37,38). 

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