Cholesterol sulfate formation

In recessive X-linked ichthyosis, the amount of cholesterol sulfate in the stratum corneum is increased due to a deficiency in cholesterol sulfatase deficiency [69,70], Lipid analysis of scales reveals a nearly 10-fold increase in the cholesterol sulfate to free cholesterol ratio as compared to healthy stratum corneum [71]. Previous x-ray diffraction studies on isolated ceramide mixtures revealed that increased cholesterol sulfate levels induce the formation of a fluid phase, which is likely to reduce the skin barrier function [72]. 

Cholesterol sulfate is another intercellular lipid. Addition of low levels of cholesterol sulfate, as observed in normal healthy stratum corneum, to lipid mixtures has little effect on the phase behavior at room temperature. However, addition of high levels of cholesterol sulfate, at levels similar to that observed in the skin disease recessive X-linked ichthyosis, promotes the formation of the long periodicity phase, induces the formation of a fluid phase, and increases the solubility of cholesterol in the lamellar phases [72,80],... 

Vitamin C also appears to be involved in the metabolism of cholesterol in another way. Through its sulfated metabolite, ascorbic acid sulfate, it appears to bring about the formation of cholesterol sulfate, a water-soluble compound that is excreted in the urine. By this means, cholesterol may be mobilized from the body tissues, with the result that there is a lowering of blood cholesterol levels. 

The formation and transformations of cholesterol and cholesterol sulfate in the placental and fetal compartments are indicated in Fig. 1. 

Fig. 21. (a) Rate constant for the hydrolysis on 0.1 N HCl of a cholesterol formate monolayer (50a). The incorporation into the film of a little long-chain sulfate (C22H46-SOi ) greatly accelerates the reaction. The calculated increases in reaction rate according to the Gouy (33) and Donnan equations are shown (b) For hydrolysis on 0.66 N HCl incorporation of CisH37N(CH3)+ into the film retards reaction because hydrogen ions are repelled from the surface (50a). 

The major bile salt of the carp, Cyprinm carpio, is 5a-cyprinol sulfate [21]. When [4- C]cholesterol was injected intraperitoneally into the carp, radioactive 5a-cyprinol was isolated from gallbladder bile [148]. It has been shown that the initial step in the major pathway for the formation of 5a-cyprinol (VI) from cholesterol (XV) is the 7a-hydroxylation of cholesterol to form cholest-5-ene-3j8,7a-diol (XVI) [149] (Fig. 4). It has also been shown that the double bond is isomerized to the A position before being reduced [150]. These in vivo studies suggest that until the intermediary formation of a A compound, presumably 7 ,12a-dihydroxycholest-4-en-3-one (XVII), the sequence of reactions in the biosynthesis of 5 -cyprinol (VI) in the carp is the same as that in the conversion of cholesterol (XV) to cholic acid (XIV) in mammals. 7a,12a-Dihydroxycholest-4-en-3-one (XVII) was found to be converted into 5a-cholestane-3a,7a,12a-triol (XVIII) by the microsomal fraction of carp hver fortified with NADPH [151]. The conversion of the triol (XVIII) to 5a-cyprinol (VI) via 27-deoxy-5a-cyprinol (XIX) was also established. The 26-hydroxylation of the triol (XVIII) was catalyzed by the microsomal fraction fortified with NADPH, and the 27-hydroxylation of 27-deoxy-5a-cyprinol (XIX) was catalyzed by the mitochondrial fraction fortified with NADPH [151]. 

Although cholesterol is the major source of 5)9-bile acids, an unsaturated acid, 3)8-hydroxy-5-cholenic acid [174] has been found in meconium, mainly as the sulfate [175], in bile of a boy with a deficiency of 3)8-hydroxysteroid dehydrogenase [176], and in urine of healthy persons and individuals with liver disease [164]. The details of metabolism of 3)8-hydroxy-5-cholenic acid to lithocholate have not been entirely elucidated, but the mechanism for conversion of the 3/8-hydroxy-A to the 3-oxo-A derivative has been formulated in the C27 series (cf. Chapter 9). Briefly, the 3)8-ol is dehydrogenated by a microsomal enzyme fortified with NAD to provide the 3-oxo-A system [177,178]. Whether a A - A" isomerase is essential is not known, since there is no direct evidence for the formation of the intermediary 3-oxo-A system the rate-limiting step is the dehydrogenation of the 3)8-ol which may prevent accumulation of the 3-oxo-A system [177]. The reduction of the double bond at 4-5 to the 5)8- or 5a-bile acid is catalyzed by the respective A -3-oxosteroid 5)8- or 5 -reductase obtained from liver cytosol [170], and has been purified about 10-fold [178]. The formation of the 3-oxo-5/9 derivative requires the enzyme and NADPH the proton from the A side (4A-NADPH) appeared in the product as the 5)8-H, whereas the proton at C-4 is derived from the aqueous medium. Formation of the 5a derivative requires (4B-NADPH) in a similar mechanism (Fig. 4) [179], Reduction of the 3-0X0 product is then catalyzed by 3a-hydroxysteroid dehydrogenase as discussed above. 

FIGURE 14.7 Derivatization for ESI-MS/MS. (A) Preparation of the dimethylaminoethylester of dihydroxycholestanoic acid bis acetate. (B) Preparation of aminoethanesulfonate derivative of chenodeoxycholic acid. (C) Formation of sulfate ester of cholesterol. (D) Preparation of oxime of testosterone. 

Steroids are derived from the same squalene precursor and have an oxygen-dependent biosynthetic pathway beginning with the formation of the first intermediate, 2,3-oxidosqualene (for details, see Sect. 5.1). Sterols, also known as steroid alcohols, are a subclass of steroids and may be found either as fi ee sterols, acylated, alkylated, sulfated, or linked to a glycoside moiety which can be itself acylated. Sterol biosynthesis is nearly ubiquitous among eukaryotes but almost completely absent in prokaryotes. As a result, the presence of diverse steranes (saturated four-cycle skeleton) in ancient rocks has been considered as evidence for over 2.7 billion years of eukaryotic evolution. Cholesterol is the most well-known sterol found in animal cell membranes (for establishing proper membrane permeability and fluidity) and red blood cells. 

Oxidation of LDL cholesterol is one of the key steps in the initiation of atherosclerotic lesions by promoting injury to the arterial wall through several mechanisms, including growth factor and chemotactic protein expression, inflammation, and increased local macrophages [140]. Visioli et al. [117] have demonstrated that OL and HT strongly inhibit copper sulfate-induced oxidation of LDL, as result of measure of various indexes of lipid oxidation (vitamin E content, formation of thiobarbituric acid-reacting substances, lipid peroxides, levels of... 

The treatment using novel ACAT inhibitor pactimibe sulfate (CS-505), avasimibe (CI-1011) (Fig.6), and a potent bile acid binding resin cholestyramine directly affects macrophages in atherosclerotic lesions. They would limit the increase in intracellular free cholesterol by its TC-lowering effect. This would allow free cholesterol to excrete into HDL, restoring the cholesterol influx/efflux balance, thus preventing foam cell formation. (Terasak N. et al. 2007). 

Chondroitin sulfate proteoglycan-LDL completes are taken up rapidly by macrophages [33, 34] and smooth muscle cells [35]. Such uptake leads to the accumulation of intracellular lipid and the formation of foam cells which are characteristically found in atherosclerotic lesions. Internalization of CSPG-LDL complexes takes place via LDL receptor dependent and independent pathways and is accompanied by decreased degradation of the internalized LDL and increased cholesterol ester synthesis. Thus, proteoglycans not only promote the extracellular retention of lipoproteins but the intracellular retention as well. 

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