Phytosterols absorption

While assessing the contributions of alternative scenarios described above is important to understanding the mechanism of drug action, assessing the benefit or risk posed by the overall effect is a slightly different process. With respect to the first case described above, increased phytosterol absorption due to... 

Borel, R, Factors affecting intestinal absorption of highly lipophilic food microconstituents (fat-soluble vitamins, carotenoids and phytosterols), Clin. Chem. Lab. Med., 41, 979, 2003. 

Ezetimibe is the first drug in a new class of agents referred to as cholesterol absorption inhibitors. Ezetimibe blocks biliary and dietary cholesterol as well as phytosterol (plant sterol)... 

Ezetimibe is the first member of a group of drugs that inhibit intestinal absorption of phytosterols and cholesterol. Its primary clinical effect is reduction of LDL levels. In one trial, patients receiving ezetimibe in combination with simvastatin had marginal, but not statistically significant, increases in carotid intimal-medial thickness (IMT) compared with those... 

Ezetimibe is a selective inhibitor of intestinal absorption of cholesterol and phytosterols. A transport protein, NPC1L1, appears to be the target of the drug. It is effective even in the absence of dietary cholesterol because it inhibits reabsorption of cholesterol excreted in the bile. 

Mel nikov, S.M., Seijen ten Hoorn, J.W., and Bertrand, B. 2004b. Can cholesterol absorption be reduced by phytosterols and phytostanols via a cocrystallization mechanism Chem. Phys. Lipids 121, 15-33. 

Ezetimibe is the first member of a new group of drugs that inhibit intestinal absorption of phytosterols and cholesterol. Its primary clinical effect is reduction of LDL levels. 

Key words Cholesterol absorption, phytosterols, cholesterol excretion, reverse cholesterol transport, ACAT, CEL, inhibitors, bile acids, fecal sterols, dual label, obesity, cardiovascular disease. 

For cholesterol absorption, one can take advantage of the fact that plant sterols (phytosterols) are poorly absorbed by mice and humans despite close structural similarity to cholesterol. Beta sitosterol, for example, differs from cholesterol only by the addition of an ethyl group to carbon 24 of the sterol side chain (see Fig. 10.1). This reduces absorption to 6% (34, 35) as compared to 60-80% for cholesterol. Sitostanol, which has a saturated C5-C6 bond in addition to the ethyl group, is only absorbed at 3% (34, 35) and is widely used as a non-absorbed sterol marker (Fig. 10.1). 

Fig. 10.1. Structures of cholesterol and a commonly used phytosterol. Adding a branch to the side chain and removing the double bond in the sterol B ring combine to reduce absorption of sitostanol —20-fold as compared to cholesterol.

Feces collection return the mice to their respective cages and collect feces for 24 h (see Note 3). Longer collection times have the potential to underestimate absorption since some absorbed cholesterol will end up in HDL and subsequently be taken up by the liver, transported to the bile, and secreted into the intestine. However, semi-purified diets are usually very low in fiber, which may reduce intestinal motility. If necessary, sterol transit time is measured in a preliminary experiment where only radiolabeled phytosterol is given and total fecal output is collected on days 1, 2, and 3. Sterols are quantitatively extracted (see below Section 3.1.3) and the time for 90% excretion determined. 

Sanders, D. J., Minter, H. J., Howes, D., and Hepburn, P. A. (2000) The safety evaluation of phytosterol esters. Part 6. The comparative absorption and tissue distribution of phy-tosterols in the rat. Food Chem. Toxicol. 38, 485 91. 

The esterification of either of the sterols enhances its solubility in a hydrophilic environment. This modification makes the phytosterol a more active ingredient when used to fortify edible products that lower serum cholesterol. The cholesterol-lowering action of (3-sitosterol was first reported more than 40 years ago (Farquhar et al., 1956). The differences between the plant sterols and the cholesterol include the addition of an ethyl group to the aliphatic side-chain of both sterols. Saturation of the double bond in the second ring of (3-sitosterol yields sitostanol. The presence of the ethyl group on the side-chain increases the hydrophobicity of both phytosterols such that it is greater than the hydrophobicity of the base molecule, cholesterol. This increase in hydrophobicity is expected to decrease the absorption of... 

Phytosterols are structurally very similar to cholesterol and the major phytosterols (campesterol, sitosterol and stigmasterol) have the same kind of membrane viscosity modulating function in plants that cholesterol (C27 3-OH-C6 C6 G61 C5—C8) has in animals. Campesterol (24-methylcholesterol), sitosterol (24-ethylcholesterol) and stigmasterol (A22, 24-ethylcholesterol) are widespread phytosterols. The animal sterols lanosterol and cholesterol are present in particular plants. Phytosterol esters reduce cholesterol absorption and lower LDL-cholesterol. 

Lin, X. Ma, L. Racette, S.B. Anderson Spearie, C.L. Ostlimd, R.E. Jr., 2009. Phytosterol glycosides reduee eholesterol absorption in humans. Am. J. Phys. Gastroin. Liver Phys. 296 G931-G935. 

Phytosterols are partially absorbed in the small intestine. Human absorption efficiency is estimated to be approximately 10% for campesterol and campestanol, 4 to 5% for sitosterol and stigmasterol, and negligible for sitostanol. The absorption of cholesterol ranges from 33 to 60%. Structural features, including the length and configuration of the aliphatic side chain of phytosterols, are thought to contribute to the differences in the absorption efficiency between phytosterols and cholesterol. " Phytosterols apparently displace cholesterol by mass action and... 

Phytosterols are safe when consumed in moderate amounts, such as those used in human studies, lu humans, phytosterol intakes of up to 25 g/d for several mouths were uot associated with adverse health effects. Phytosterol-fortilied foods should be avoided by iudividuals with phytosterolemia, an extremely rare genetic disorder characterized by imusuaUy high rates of intestinal absorption of phytosterols and an increased risk of premature atherosclerosis. ... 

A concern has been raised that phytosterol doses that are effective for cholesterol reduction may impair the absorption and lower blood concentrations of fat-soluble vitamins and antioxidants. A number of studies showed that phytosterols had no effect on plasma concentrations of vitamin D, retinol, or plasma-lipid-standardized alpha-tocopherol. Moreover, the reports of the effect of phytosterols on concentrations of blood carotenoids (lutein, lycopene, and alpha-carotene) are controversial. There seems to be general agreement that phytosterol doses >1 g/d significantly decrease LDL-C standardized beta-carotene concentrations however, it remains to be determined whether a reported 15-20% reduction in beta-carotene due to phytosterol supplementation is associated with adverse health effects. Noakes et al. found that consumption of one or more carotenoid-rich vegetable or fruit servings a day was sufficient to prevent lowering of plasma carotenoid concentrations in 46 subjects with hypercholesterolemia treated with 2.3 g of either sterol or stanol esters. 

For food applications, stands are synthetically derived from plant sterols. Although the naturally occurring amounts of phytosterols in 30 g of com oil are sufficient to inhibit cholesterol absorption, """ it is not clear whether natural intakes of phytosterols significantly lower plasma LDL-C concentrations. The relatively greater intake of phytosterols by vegetarians may contribute to the lower LDL-C levels commonly observed in this population. It would, however, be nearly impossible for most individuals to obtain more than 1 g of phytosterols from food without iugesting large quantities of food. Com oil is a rich source of phytosterols, yet one would have to consume about 100 g (900 kcal) of com oil per day in order to obtain 1 g/d of phytosterols. 

Ostlund, R.E., Jr. et al.. Phytosterols that are naturally present in commercial com oil significantly reduce cholesterol absorption in humans. Am. J. Clin. Nutr., 75, 1000, 2002. 

So, one mode of action for the phytosterols is to inhibit or completely block absorption of dietary cholesterol into the bloodstream. But they work in another, entirely different, way as well. That s by preventing the recycling of bile, made from cholesterol, following a meal. Phytosterols attach to the bile, which is then eliminated in the bowel movement. That s why taking the plant sterols improves cholesterol levels even when they re used before meals that have little or no cholesterol at all. 

The immediate-release formulation of phytosterols is made by Endurance Products Company, based outside of Portland, Oregon. Its Web site is www.endur.com. This is the same company that makes the best formulation of my favorite method of cholesterol control, niacin. Place orders outside the United States at www. endur.com click on Customer Service page. International Orders. Take two 450 mg tablets at the start of two major meals daily to block the absorption of cholesterol in the foods you eat, inhibit the recycling of bile made of cholesterol, and achieve a cholesterol reduction in your bloodstream of up to 10 percent. 

A typical Western diet contains approximately 100-300 mg and 20-50 mg of plant sterol and plant stanol, respectively. The relationship between total dietary phytosterol content and the fatty acid composition of the diet decreases with increasing saturated fatty acids, whereas the total dietary phytosterol content increases with increasing PUFA (89). Fortification of lipid foods, such as margarine, with plant sterols will dramatically increase the daily intake of phytosterols and significantly lower serum cholesterol (90). The dietary consumption of large amounts of plant sterols will interfere with cholesterol absorption, thereby leading to an increased daily neutral steroid excretion. 

Canola oil contains a relatively high level of phytosterols (892 mg/100 g), about twice the level in soybean oil or sunflower oil (436 and 496 mg/100 g respectively) (Table 8). p-Sitosterol accounts for about 50%, campesterol 35%, and brassicasterol 14% of the total phytosterols in canola oil. Canola oil is the only common vegetable oil that contains brassicasterol. Plant sterols have been reported to lower plasma cholesterol level (107) by inhibiting the absorption of dietary cholesterol and the reabsorption of biliary cholesterol (108). 

Phjdosterols and cholesterol have similar structures phytosterols are therefore competitors of cholesterol absorption. Consumption of phytosterol may lower blood cholesterol and thus protect from cardiovascular diseases (29). Phytosterol, especially, p-sitosterol, inhibits the growth of human colon cancer cell (30), prostate cancer cell (31), and breast cancer cell (32). 

The distillate obtained from sunflower oil may be sold to pharmaceutical companies for tocopherol and sterol isolation. Tocopherols may be used as natural antioxidants or may be converted to vitamin E by methylating the heterocyclic ring. The interest in phytosterols is caused by the high potential of some of them to inhibit intestinal cholesterol absorption. 

During the early 1950s, it was reported that phytosterols lower serum cholesterol (173-175). This effect was appreciated as a possible protection strategy against car-divascular disease risk after the results of several convincing animal and human studies (176-184). Studies have shown that a daily intake of 2-g phytosterol or phytostanol causes 40-50% reduction in the dietary cholesterol absorption, 6-10% reduction in total serum cholesterol, and 8-14% reduction in the semm low-density lipoprotein cholesterol (37, 185-187). 

The mechanism for the inhibition of cholesterol absorption is thought to involve competitive transfer to the micellar phase during absorption from the intestinal lumen. Phytosterols in the micellar phase may also act as emulsifying agents that selectively inhibit the transfer of cholesterol and other lipids (e.g., carotenoids and vitamins) and, thereby, limit their absorption. The exact kinetics governing the sterol competition for transfer are not known, but dietary sterols are absorbed differently in the digestive tract 40-50% for cholesterol, 12-16% for campesterol, 4-5% sitosterol, and <0.5% for phytostanols (37). Before absorption, esterified sterols are hydrolysed effectively in the upper intestine (191). Absorbed phytosterols are excreted by the liver into the bile but are hardly converted to bile acids (192). Numerous studies in animals and humans approved the safety of phytosterols and phytostanols (37). 

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