Sterols, reduction

Free sterols are slightly less volatile than tocopherols (Figure 2). Deodorization of soybean oil under varying process conditions (temperature 220-260°C, low pressure 1.5 mbar and 1.5% steam) resulted in a 10-35% reduction of the total sterol content (20). This sterol reduction is totally attributed to the free sterol fraction because esterified sterols are not volatile under the conditions prevailing inside the deodorizer. In case of steam refining, an increase of the steryl ester content can sometimes be observed, probably because of a heat-promoted esterification reaction between free sterols and fatty acids (20). This phenomenon will not take place during deodorization of chemically neutralized oil because the initial FFA concentration is much lower in that case. 

Clotrimazole and other azole derivatives have a different mode of action than the polyenes, eg, amphotericin B. The latter biad to the ergosterol present ia the membranes of yeasts and fungi, but azole derivatives inhibit the cytochrome P-450 dependent biosynthesis of ergosterol (8—11). This inhibition not only results in a reduction of ergosterol, but also in an accumulation of C-14 methyl sterols. They disturb membrane permeabiUty, inhibit cell rephcation, and are basically responsible, in combination with the reduction of ergosterol levels, for the antifungal action. 

Miconazole. Miconazole nitrate [22832-87-7] (Fig. 2), the 1-phenethyl-imidazole derivative first described in 1969, interferes at low doses with the cytochrome P-450 dependent ergosterol biosynthesis in yeasts and fungi. The result is accumulation of C-14 methylated sterols on the one hand and reduction of the ergosterol levels in the membranes on the other hand (12). Analogous to clotrimazole, this leads to a disturbance in the membranes it results in inhibition of ceU repHcation, mycelium development (in C. albicans) and finally, ceU death. High concentrations of miconazole, which may be achieved with topical use, disturb the orientation of phosphoHpids in the membranes, which produces leaks (13). 

A recent study of the reduction of cholest-4-en-3-one with an excess of NaBH4 in 2-propanol shows that the corresponding cholest-4-en-3 -ol is the major product (44% yield) 4 other compounds (5a-cholestan-3a- and -3jS-ols, a sterol, possibly 5y -cholestan-3l -ol and an unidentified hydrocarbon) have also been isolated. When the reduction is carried out in the presence of ultraviolet light cholest-4-en-3/5-ol is still the major product (34%) but 7 other products are also obtained. These results show clearly the benefit of using Li[OC(CH3)3]3AlH for the preparation of the 4-en-3 -ol. ... 

Various mechanisms have been proposed to explain the hypocholesterolemic effect of GA (Annison et al., 1995 Tiss et al., 2001). Some studies have suggested that the viscosity of fermentable dietary fiber contributes substantially to the reduction of lipids in animals and humans (Gallaher et al., 1993 Moundras et al., 1994). However, other studies suggested that this property is not related to plasma lipids (Evans et al., 1992). The mechanism involved is clearly linked to increased bile acid excretion and fecal neutral sterol or a modification of digestion and absorption of lipids (Moundras et al., 1994). 

WESTSTRATE J A, MEIJER G w (1998) Plant sterol emiched margarine and reduction of plasma and total LDL-cholesterol concentrations in normocholesterolemic and mildly hypercholesterolemic sahjects.. Eur J Clin Nutr, 52(5) 334-43. 

Therapeutic lifestyle changes should be the first approach tried in all patients (Table 9—7).3 An adequate trial of TLC should be employed in all patients, but pharmacotherapy should be instituted concurrently in higher-risk patients. This includes dietary restrictions of cholesterol and saturated fats as well as regular exercise and weight reduction. In addition, therapeutic options to enhance LDL cholesterol lowering such as consumption of plant stanols/sterols (which competitively inhibit incorporation of cholesterol into micelles) and dietary fiber should be encouraged. These therapeutic options collectively may reduce LDL cholesterol by 20% to 25%. 

The inhibitory effects of in vitro sterol addition (21) showed large percentage kills (83% and 91% respectively). The in vitro addition of ergosterol (10.1 mM) to P brevis cell cultures with Filipin (1.5 mM) showed complete inhibition of the cytolytic effect. Ergosterol (10.1 mM) added to P. brevis cell cultures with cell extract showed a 10% reduction in cell mortality. The addition of ergosterol alone (control) showed no cytolytic effect at the experimental concentration (10.1 mM). 

In more recent studies the use of HPLC allowed isolation and counting of individual sterols after administration of labelled precursors. The sterols isolated from mantles and viscera of the nudibranch Doris verrucosa were identified as cholestanol, cholesterol, 24-dehydrocholesterol and 7-dehydrocholesterol [103]. After injection of dl-[2-14C]-mevalonic acid DBED salt, cholesterol (57) and 7-dehydrocholesterol (58) were isolated as the acetates by reversed phase HPLC. Both sterols were found significantly labelled specific radioactivity associated with 7-dehydrocholesterol was higher by one order of magnitude than that associated with cholesterol. This fact would indicate either that the reduction of the A1 double bond of 7-dehydrocholesterol to afford cholesterol occurs at a low rate, or that the cholesterol found in D. verrucosa comes partly from a dietary source. 

A less common reactive species is the Fe peroxo anion expected from two-electron reduction of O2 at a hemoprotein iron atom (Fig. 14, structure A). Protonation of this intermediate would yield the Fe —OOH precursor (Fig. 14, structure B) of the ferryl species. However, it is now clear that the Fe peroxo anion can directly react as a nucleophile with highly electrophilic substrates such as aldehydes. Addition of the peroxo anion to the aldehyde, followed by homolytic scission of the dioxygen bond, is now accepted as the mechanism for the carbon-carbon bond cleavage reactions catalyzed by several cytochrome P450 enzymes, including aromatase, lanosterol 14-demethylase, and sterol 17-lyase (133). A similar nucleophilic addition of the Fe peroxo anion to a carbon-nitrogen double bond has been invoked in the mechanism of the nitric oxide synthases (133). 

Plant sterols such as stigmasterol typically contain an extra ethyl group when compared with cholesterol. Now this is not introduced by an electrophilic ethylation process instead, two successive electrophilic methylation processes occur, both involving SAM as methyl donor. Indeed, it is a methylene derivative like that just seen in ergosterol formation that can act as the alkene for further electrophilic alkylation. After proton loss, the product has a side-chain with an ethylidene substituent the side-chains of the common plant sterols stigmasterol and sitosterol are then related by repeats of the reduction and dehydrogenation processes already seen in ergosterol formation. 

Cell suspension cultures of Gypsophila paniculata and Saponaria officinalis produce very closely related triterpenoid saponins. Pretreatment of cell suspension cultures of G. paniculata with gypsogenin 3,0-glucuxonide (a triterpenoid saponin precursor in G. paniculata) followed by administration of [ C] acetate resulted in a marked reduction in incorporation of radioactivity into saponins and their precursors, but not into sterols and steryl glycosides [26]. Measurements of OSC activities revealed that there was no effect of elicitor treatment on CS levels in either species, but in G. paniculata AS levels went down while in S. officinalis they increased. This suggests that in these two species OSCs are regulating steps in the isoprenoid pathway and control the flux to sterols and triter-penes. 

Arnqvist, L., Dutta, P. C., Jonsson, L., Sitbon, F. (2003). Reduction of cholesterol and glycoalkaloid levels in transgenic potato plants by overexpression of a type 1 sterol methyltransferase cDNA. Plant Physiol., 131, 1792-1799. 

Also known as statins. HMG CoA reductase (Hydroxymethyl-Glutaryl Coenzyme A Reductase) inhibitors block the synthesis of cholesterol in liver by competitively inhibiting HMG CoA reductase activity, also cause depletion of critical intracellular pools of sterols and increased transcription of LDL receptors leading to enhanced removal from plasma of LDL cholesterol and LDL precursors. They also reduce hepatic synthesis of VLDL, increase plasma HDL. Reduction of LDL occurs over 4-6 weeks. 

Synthesis of the 24R isomer was commenced by stereoselective hydroxymethy-lation of the enolate of lactone 30. Introduction of methyl groups at C25 and C26 was achieved by addition of MeLi to give 24R depresosterol (33). Alternatively, trapping of the lactone enolate with acetone followed by LiAlH reduction gave the 245 epimer (34). Spectral comparison indicated that the 24R sterol is identical with the natural product. 

In fungi, ergosterol, synthesised from acetyl-CoA, is the major sterol (Figure 4.2 Mercer2) and has an essential role in the maintenance of membrane function such that a reduction in its availability disrupts membrane integrity. 

Reductive synthesis of fatty acids, steroids, sterols [ Cytochrome P450 system... 

Rearrangement has never been observed without the accompanying reduction.310-313 More complex rearrangements that occur during biosynthesis of sterols are described in Chapter 22. 

Since cholesterol is an important component of many biological membranes mixtures of polymerizable lipids with this sterol are of great interest. In mixed monolayers of natural lipids with cholesterol a pronounced condensation effect , i.e. a reduction of the mean area per molecule of phospholipid is observed68. This influence of cholesterol on diacetylenic lecithin (18, n = 12), however, is not very significant (Fig. 32). Photopolymerization indicates phase separation in this system. Apparently due to the large hydrophobic interactions between the long hydrocarbon chains of... 

The C>4 bile acids arise from cholesterol in the liver after saturation of the steroid nucleus and reduction in length of the side chain to a 5-carbon add they may differ in the number of hydroxyl groups on the sterol nucleus. The four acids isolated from human bile include cholic acid (3,7,12-tiihydroxy), as shown in Fig. 1 deoxycholic acid (2,12-dihydroxy) chenodeoxycholic acid (3,7-dihydroxy) and lithocholic acid (3-hydroxy). The bile acids are not excreted into the bile as such, but are conjugated through the C24 carboxylic add with glycine or... 

The last sequence of reactions in the biosynthesis of choles-terol involves approximately 20 enzymatic steps, starting with lanosterol. In mammals the major route involves a series of double-bond reductions and demethylations (fig. 20.10). The sequence of reactions involves reduction of the A24 double bond, the oxidation and removal of the 14a methyl group followed by the oxidation and removal of the two methyl groups at position 4 in the sterol. The final reaction is a reduction of the A7 double bond in 7-dehydro-cholesterol. An alternative pathway from lanosterol to cholesterol also exists. The enzymes involved in the transformation of lanosterol to cholesterol are all located on the endoplasmic reticulum. 

Soybean-derived sterol mixture (SS), soybean-derived steryl glucosides (SG), and their individual components have been extensively studied for their ability to promote the nasal absorption of drugs, particularly insulin [79,80], Maitani et al. [79] demonstrated that the nasal administration of SG plus insulin to rabbits resulted in significant reductions in blood glucose. The effect of SG was dose dependent to 1%, with a plateau being reached thereafter. Muramatsu et al. [81] have demonstrated that SG perturbs the phospholipids in artificial membranes (i.e., liposomes). Furthermore, circular dichroism studies with insulin in the presence or absence of SG have indicated that the enhancer had little effect on the dissociation of insulin hexamers to monomers. These results suggest that the action of SS and SG involves interaction with the nasal membrane rather than interaction with insulin molecules. 

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