Sitosterol, absorption

The practical development of plant sterol drugs as cholesterol-lowering agents will depend both on structural features of the sterols themselves and on the form of the administered agent. For example, the unsaturated sterol sitosterol is poorly absorbed in the human intestine, whereas sitostanol, the saturated analog, is almost totally unabsorbable. In addition, there is evidence that plant sterols administered in a soluble, micellar form (see page 261 for a description of micelles) are more effective in blocking cholesterol absorption than plant sterols administered in a solid, crystalline form. 

Maitani, Y., et al. 2000. The enhancing effect of soybean-derived sterylglucoside and beta-sitosterol beta-D-glucoside on nasal absorption in rabbits, Int J Pharm 200 17. 

Heinemann, T., Pietruck, B., Kullak-Ublick, G., and von Bergmann, K. 1988. Comparison of sitosterol and sitostanol on inhibition of intestinal cholesterol absorption. Agents Actions... 

Ikeda, I. and Sugano, M. 1983. Some aspects of mechanism of inhibition of cholesterol absorption by -sitosterol. Biochim. Biophys. Acta 732, 651-658. 

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). 

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... 

The proportions of delta 8-cholesterol and desmosterol in the serum rose while those of cholestanol, campesterol and sitosterol dropped, implying a decreased absorption of cholesterol and a compensatory increase in its synthesis. High basal precursor sterol proportions were predictive of a large decrement in titer of LDL cholesterol. It appeared that partial substitution of normal dietary lipid consumption with sitostanol was a safe and effective therapeutic measure for children with FH (Lees et al., 1977 Wang and Ng, 1999). The effect of a small amount of sitosterol, sitostanol and sitostanol esters dissolved in rapeseed oil on serum lipids and cholesterol metabolism in patients with primary hypercholesterolemia and various apolipoprotein E phenotypes on a rapeseed oil diet showed a diminution in TC and LDL-cholesterol levels in the serum (Gylling and Miettinen, 1994). 

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. 

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... 

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 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). 

Sitosterol. Sitosterol is a plant sterol, who.se structure is identical with that of cholesterol, except for the sub.stitutcd ethyl group on C-24 nf its side chain. Although the mechanism of its hypolipidemic effect is not clearly understood, it is suspected that the drug inhibits the absorption of dietary cholesterol from the gastrointestinal iraci. Sitosterols are absorbed poorly from the mucosal lining and appear to compete with cholesterol fnr absorption sites in the intestine. 

In addition to animal cholesterol, approximately 200 to 300 mg of plant sterols are ingested daily. The most common plant sterol is P-sitosterol. Plant sterols differ from cholesterol only by small variations on the sterol side chain. Despite their close similarity to cholesterol, plant sterols are poorly absorbed. When plant sterols are administered in amounts of 5 to 15g/day, they significantly inhibit the absorption of cholesterol. Although the mechanism for reducing cholesterol absorption has not been determined, plant sterols have been used therapeutically in patients with elevated plasma cholesterol levels. 

Ntanios, F. Y. and Jones, P. J. H. 1999. Dietary sitosterol reciprocally influences cholesterol absorption and biosynthesis in hamsters and rabbits. Atherosclerosis 143, 341-351. 

A dissociation between HMG-CoA reductase and the cholesterol 7a-hydroxylase has been reported in connection with feeding of cholesterol, tomatidine, sitosterol as well as in scurvy. Feeding cholesterol inhibits HMG-CoA reductase and in most [99,222,238,239] but not all [50] studies a stimulatory effect has been found on cholesterol 7a-hydroxylase. The stimulatory effect may be due to an expansion of the pool of cholesterol available for cholesterol 7a-hydroxylase. Feeding with tomatidine and sitosterol interferes with absorption of cholesterol from the intestine, and the increased HMG-CoA reductase activity is probably due to decreased inhibition by lymph cholesterol [240,241]. The cholesterol 7a-hydroxylase activity is only slightly increased or unaffected under these conditions [240,241]. 

The at one time superfluous sitosterol 11-2 has found minor use as a drug for treating elevated cholesterol levels by inhibiting the absorption of dietary cholesterol. Methods have been developed within the past decade for converting sitosterol to androst-4-ene-17,20-dione (12-1) by fermentation (Scheme 2.12). 

Phytosterols, especially sitostanol, are known inhibitors of cholesterol absorption [2]. The major sterols belonging to the group of 4-desmethylsterols are campesterol (24a-methyl-5-cholesten-3P-ol), sitosterol (24a-ethyl-5-cholesten-3P-ol), canpestanol (24a-methyl-5oc-cholestan-3p-ol) and sitostanol (24a-ethyl-5a-cholestan-3P-ol). The saturated counterparts of campesterol and sitosterol are campestanol and sitostanol, commonly known as stanols. 

Ezetimibe is an antihyperlipidemic agent that inhibits absorption of cholesterol by the small intestine. It is indicated to be administered alone or with HMG-CoA reductase inhibitors as adjnnctive therapy to diet for reduction of elevated total cholesterol, LDL, and apolipoprotein (Apo) in patients with primary hypercholesterolemia with atorv-astatin or simvastatin for the reduction of elevated total cholesterol and LDL levels in patients with homozygous familial hypercholesterolemia as an adjunct to other lipidlowering treatments or if such treatments are unavailable and as adjnnctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygons familial sitosterolemia. 

Recent data indicate that ezetimibe inhibits a specific transport process in jejunal enterocytes, which take up cholesterol from the lumen. The putative transport protein is Niemann-Pick Cl-hke 1 protein (NPCILI). In wild-type mice, ezetimibe inhibits cholesterol absorption by about 70% in NPCILI knockout mice, cholesterol absorption is 86% lower than in wild-type mice, and ezetimibe has no effect on cholesterol absorption. Ezetimibe does not affect intestinal triglyceride absorption. In human subjects, ezetimibe reduced cholesterol absorption by 54%, precipitating a compensatory increase in cholesterol synthesis, which can be inhibited with a cholesterol synthesis inhibitor such as a statin. There is also a substantial reduction of plasma levels of plant sterols (campesterol and sitosterol concentrations are reduced by 48 and 41%, respectively), indicating that ezetimibe also inhibits intestinal absorption of plant sterols. 

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