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PubMed2006

Role of cholesterol in amyloid cascade: cholesterol-dependent modulation of tau phosphorylation and mitochondrial function.

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the epsilon4 allele increasing and the epsilon2 allele decreasing the risk of developing AD. ApoE is the major apolipoprotein that modulates cholesterol transport in the central nervous system, cholesterol being an essential component of membranes for maintaining their structure and functions. Epidemiological studies have suggested a link between serum cholesterol levels and AD development and the potential therapeutic effectiveness of statins for AD; and furthermore, biological studies have shown that amyloid beta-protein (Abeta) secretion is modulated by cellular cholesterol level. However, other lines of evidence show controversial results. In addition to the role of cholesterol in Abeta generation, different interactions of cholesterol with Abeta and its role in AD pathogenesis have been shown, i.e. Abeta affects cholesterol dynamics in neurons, and altered cholesterol metabolism in turn leads to neurodegeneration with abnormally phosphorylated tau (tauopathy). In this review, the reciprocal interactions between cholesterol and Abeta, and the role of cholesterol in tauopathy are discussed. The isoform-specific involvement of apoE in this cascade, in which high-density lipoprotein-like particles are generated and supplied to neurons to maintain cholesterol homeostasis, is also discussed.

Alzheimer Disease↗

PubMed1986

Dietary cholesterol, serum cholesterol, and colon cancer: a review.

Observational and case-control epidemiologic data supported by experimental studies indicate that dietary cholesterol may contribute to colon tumorigenesis. A mechanism for this possible relationship is currently under investigation. Additional international epidemiologic data, although not uniformly consistent, indicate an inverse relationship between serum or plasma cholesterol levels and risk for colon cancer. This risk is greatest at serum cholesterol levels of less than 180 mg/dl. It has been suggested but not proven that individuals consuming diets high in dietary fat and cholesterol may have variations in cholesterol dynamics that account for lowered serum cholesterol levels and enhanced risk for colon cancer. Clinical evidence in both men and women indicates that age-sex-adjusted, low serum cholesterol levels may precede the detection of colon cancer by more than 5 years. Preclinical colon cancer is associated with a further decrease in serum cholesterol levels. It is not clear whether progression of the disease before metastatic spread results in continued lowering of serum cholesterol levels. In men with markedly elevated serum cholesterol levels who have been placed on cholesterol-lowering drugs such as clofibrate or cholestyramine, there was no evidence that such regimens increased the risk for colon cancer. It is possible that reductions in serum cholesterol associated with the use of these drugs are insufficient to lower cholesterol levels to a range associated with an increased risk for colon cancer.

Cholesterol↗

PubMed1985

Effects of cycloartenol on absorption and serum levels of cholesterol in rats.

The possibility that cycloartenol magnifies the hypocholesterolemic effect of beta-sitosterol was studied in two strains of rats fed on cholesterol-enriched (0.5%) diets. Cycloartenol was added to diets containing 1.0% or 0.5% beta-sitosterol at the 0.05% level and to diet free of plant sterol at the 0.5% level. In one experiment, diets included sodium cholate (0.125%). Due to the potent hypocholesterolemic efficacy of beta-sitosterol under the present dietary regimens, no clear additional effect (so-called synergistic effect) of cycloartenol was observed. However, in the experiment using Wistar rats, the decrease in serum apo A-I due to feeding cholesterol was ameliorated more effectively in combination with beta-sitosterol than with beta-sitosterol alone. The hepatic deposition of cholesterol was mitigated by dietary beta-sitosterol, and further, although slightly, by a combination of beta-sitosterol and cycloartenol, except in the experiment with diets containing sodium cholate. Fecal excretion of neutral and acidic steroids was not meaningly magnified by cycloartenol. Cycloartenol itself was not as effective as beta-sitosterol in mitigating lipid disorders due to dietary cholesterol. The rate of appearance of cholesterol in the thoracic duct lymph was not interfered with further by a combination of beta-sitosterol and cycloartenol compared to beta-sitosterol alone. This trimethylsterol was absorbed at a rate approximately 4-fold higher than that of beta-sitosterol, though much lower compared to cholesterol. These results suggest a preference for cycloartenol in cholesterol dynamics. However, cycloartenol seems unlikely to influence cholesterol absorption in the small intestine.

Animals↗

PubMed1989

Hypocholesterolemic activity of alpha-amylase hydrolysate of bagasse alkaline extract in rats fed atherogenic diet.

Cholesterol-lowering activity of enzymatic hydrolysate of bagasse alkaline extract was studied in rats fed a cholesterol-enriched diet. The bagasse alkaline extract was found to be vulnerable to the enzymic attack of alpha-amylase. Thus the alkaline extract was degraded into two fractions: long-chain fraction (polysaccharides) and short-chain fraction (oligosaccharides). The long-chain fraction was active in lowering the serum cholesterol level while feeding the short-chain fraction resulted in a slightly elevated serum cholesterol level. The feeding by gavege of the long-chain fraction 12 h after the meal also was effective in lowering serum cholesterol concentration. These findings were compatible with the concept that the bagasse alkaline extract affect the cholesterol dynamics apart from input-output balance of cholesterol. Possible mechanisms responsible for the cholesterol-lowering activity of the extract were discussed.

Amylases↗

PubMed2006

Gene expression profiling in vLINCL CLN6-deficient fibroblasts: Insights into pathobiology.

The CLN6 vLINCL is caused by molecular defects in CLN6 gene coding for an ER resident transmembrane protein whose function is unknown. In the present study gene expression profiling of CLN6-deficient fibroblasts using cDNA microarray was undertaken in order to provide novel insights into the molecular mechanisms underlying this neurodegenerative fatal disease. Data were validated by qRT-PCR. Statistically significant alterations of expression were observed for 12 transcripts. The two most overexpressed genes, versican and tissue factor pathway inhibitor 2, are related to extracellular matrix (ECM), predicting changes in ECM-related proteins in CLN6-deficient cells. Transcript profiling also suggested alterations in signal transduction pathways, apoptosis and the immune/inflammatory response. Up-regulated genes related to steroidogenesis or signalling, and the relationship between cholesterol dynamics and glycosphingolipid sorting, led to investigation of free cholesterol and gangliosides in CLN6-deficient fibroblasts. Cholesterol accumulation in lysosomes suggests a homeostasis block as a result of CLN6p deficiency. The cholesterol imbalance may affect structure/function of caveolae and lipid rafts, disrupting signalling transduction pathways and sorting cell mechanisms. Alterations in protein/lipid intracellular trafficking would affect the composition and function of endocytic compartments, including lysosomes. Dysfunctional endosomal/lysosomal vesicles may act as one of the triggers for apoptosis and cell death, and for a secondary protective inflammatory response. In conclusion, the data reported provide novel clues into molecular pathophysiological mechanisms of CLN6-deficiency, and may also help in developing disease biomarkers and therapies for this and other neurodegenerative diseases.

Cells, Cultured↗

PubMed1995

Cholesterol oxidation reduces Ca(2+)+MG (2+)-ATPase activity, interdigitation, and increases fluidity of brain synaptic plasma membranes.

These experiments examined effects of cholesterol oxidation on Ca(2+)+Mg(2+)-ATPase activity, Na(+)+K(+)-ATPase activity, and membrane structure of brain synaptic plasma membranes (SPM). Cholesterol oxidase [E.C.1.1.3.6 from Brevibacterium sp.] was used to oxidize cholesterol. Two cholesterol pools were identified in synaptosomal membranes based on their accessibility to cholesterol oxidase. A rapidly oxidized cholesterol pool was observed with a 1t1/2 of 1.19 +/- 0.09 min and a second pool with a 2t1/2 of 38.30 +/- 4.16 min. Activity of Ca(2+)+Mg(2+)-ATPase was inhibited by low levels of cholesterol oxidation. Ten percent cholesterol oxidation, for example, resulted in approximately 35% percent inhibition of Ca(2+)+Mg(2+)-ATPase activity. After 13% cholesterol oxidation, further inhibition of Ca(2+)+Mg(2+)-ATPase activity was not observed. Activity of Na(+)+K(+)-ATPase was not affected by different levels of cholesterol oxidation (5%-40%). SPM interdigitation was significantly reduced and fluidity was significantly increased by cholesterol oxidation. The relationship observed between SPM interdigitation and Ca(2+)+Mg(2+)-ATPase activity was consistent with studies using model membranes [7]. Brain SPM function and structure were altered by relatively low levels of cholesterol oxidation and is a new approach to understanding cholesterol dynamics and neuronal function. The sensitivity of brain SPM to cholesterol oxidation may be important with respect to the proposed association between oxygen free radicals and certain neurodegenerative diseases.

Animals↗

PubMed1979

Dietary fat-dependent changes in hepatic cholesterogenesis and the activity of 3-hydroxy-3-methylglutaryl-CoA reductase in fasted-refed rats.

Effects of various dietary fats on the activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and sterol and fatty acid synthesis from [1-14C]acetate and [2-14C]mevalonate were examined in the liver from fasted-refed rats. Rats fasted for 2 days were refed a fat-free diet or diets containing various fats (tricaprylin, trilaurin, trimyristin, tristearin, camellia oil, or safflower oil) at the 10% level for 1, 3, or 7 days. The activity of HMG-CoA reductase was restored to about one-half of the pre-fasting levels in all groups after refeeding for 1 day and increased to above the pre-fasting levels after 3 days, with the exception of safflower oil, the rise was especially noticeable when fat-free, tricaprylin, and tristearin diets were fed. After 7 days, the activity of HMG-CoA reductase, except for rats refed tristearin, was decreased to levels that were far below those observed after 1 day-refeeding. This was particularly marked with tricaprylin, trilaurin, and camellia oil. The response of sterogenesis resembled that of the reductase. Dietary fat-dependent modification of fatty acid synthesis from [1-14C]acetate was first demonstrated after 7 days. Hepatic esterified cholesterol tended to accumulate and the deposition was marked after 3 days of refeeding. However, fat-dependent alterations of this parameter were remarkable on day 7. The concentration of plasma cholesterol also showed dietary fat-dependent changes after refeeding. Dietary fats appear to play an important role not only in the regulation of hepatic HMG-CoA reductase and sterol synthesis, but also in the overall processes of cholesterol dynamics.

Animals↗

PubMed2003

Cholesterol paradox: is high total or low HDL cholesterol level a risk for Alzheimer's disease?

Cholesterol is an essential component of membranes for maintaining their structure and functions. The discovery that possession of apolipoprotein E (apoE), allele epsilon4 is a strong risk factor for Alzheimer's disease (AD) leads us to focus on the role of cholesterol in the pathogenesis of AD. Accumulating epidemiological and biological evidence suggests the link between the serum cholesterol level and the development of AD, and the potential therapeutic effectiveness of statins for AD and mild cognitive impairment (MCI), whereas other lines of evidence show controversial results. Cholesterol is known to interact with amyloid beta-protein (Abeta) in a reciprocal manner: cellular cholesterol levels modulate Abeta generation, whereas Abeta alters cholesterol dynamics in neurons, leading to tauopathy. In this review, the relationship between the cholesterol levels in serum or cerebrospinal fluid (CSF) and the induction of AD is discussed. The mechanism(s), if this is the case, of how cholesterol in the central nervous system (CNS) is involved in the induction of pathologies of AD including Abeta generation and tauopathy, and how statins prevent it are also discussed.

Alzheimer Disease↗

PubMed2002

Dynamics of lysosomal cholesterol in Niemann-Pick type C and normal human fibroblasts.

The dynamics of endolysosomal cholesterol were investigated in Niemann-Pick type C (NPC) cells and in human fibroblasts treated with class 2 amphiphiles to mimic NPC cells. We showed through new approaches that the massive pools of endolysosomal cholesterol in these cells are not trapped but, rather, circulate to the cell surface at about the normal rate. This flux spared NPC and amphiphile-treated cells from disruption by the extraction of their plasma membrane cholesterol with cyclodextrin. Nocodazole, a microtubule-depolymerizing agent, reversed the resistance of NPC and U18666A-treated cells to cholesterol depletion, apparently by reducing the flux of endolysosomal cholesterol to the plasma membrane. Neither nocodazole nor bafilomycin A1 (an inhibitor of the vacuolar proton pump) acted in the same way as the NPC mutation or class 2 amphiphiles: both agents decreased plasma membrane cholesterol at the expense of the endolysosomal pool and both blocked the actions of the amphiphile, U18666A. Finally, the resistance of NPC cells to lysis by amphotericin B was shown not to reflect a reduction in plasma membrane cholesterol arising from a block in lysosomal cholesterol export but rather the diversion of the amphotericin B to cholesterol-rich endolysosomes. We conclude that the large pool of endolysosomal cholesterol in NPC and amphiphile-treated fibroblasts is dynamic and that its turnover, as in normal cells, is dependent on microtubules.

Amphotericin B↗

PubMed2002

The C-terminal domain of perfringolysin O is an essential cholesterol-binding unit targeting to cholesterol-rich microdomains.

There is much evidence to indicate that cholesterol forms lateral membrane microdomains (rafts), and to suggest their important role in cellular signaling. However, no probe has been produced to analyze cholesterol behavior, especially cholesterol movement in rafts, in real time. To obtain a potent tool for analyzing cholesterol dynamics in rafts, we prepared and characterized several truncated fragments of theta-toxin (perfringolysin O), a cholesterol-binding cytolysin, whose chemically modified form has been recently shown to bind selectively to rafts. BIAcore and structural analyses demonstrate that the C-terminal domain (domain 4) of the toxin is the smallest functional unit that has the same cholesterol-binding activity as the full-size toxin with structural stability. Cell membrane-bound recombinant domain 4 was detected in the floating low-density fractions and was found to be cofractionated with the raft-associated protein Lck, indicating that recombinant domain 4 also binds selectively to cholesterol-rich rafts. Furthermore, an enhanced green fluorescent protein-domain 4 fusion protein stains membrane surfaces in a cholesterol-dependent manner in living cells. Therefore, domain 4 of theta-toxin is an essential cholesterol-binding unit targeting to cholesterol in membrane rafts, providing a very useful tool for further studies on lipid rafts on cell surfaces and inside cells.

Amino Acid Sequence↗

PubMed2000

Manganese-bilirubin effect on cholesterol accumulation in rat bile canalicular membranes.

Manganese-bilirubin (Mn-BR)-induced cholestasis in rats is associated with altered lipid composition of various hepatic subcellular fractions. Increased bile canalicular (BCM) cholesterol content in Mn-BR cholestasis and the intracellular source of the accumulating cholesterol were investigated. To label the total hepatic cholesterol pool, male Sprague-Dawley rats were given ip 3H-cholesterol, followed 18 h later by 2-14C-mevalonic acid (a precursor of cholesterol synthesis). To induce cholestasis, manganese (Mn, 4.5 mg/kg) and bilirubin (BR, 25 mg/kg) were injected iv; animals were killed 30 min after BR injection; canalicular and sinusoidal membranes, microsomes, mitochondria, and cytosol were isolated. Total cholesterol content of each fraction was determined by spectrophotometric techniques as well as radiolabeled techniques. In Mn-BR cholestasis, the total cholesterol concentrations of BCM and cytosol were significantly increased. Also, the contribution of 14C-labeled cholesterol (newly synthesized cholesterol) was enhanced in all isolated cellular fractions. The results are consistent with the hypothesis that accumulation of newly synthesized cholesterol in BCM is involved in Mn-BR cholestasis. An enhanced rate of synthesis of cholesterol, however, does not appear to be the causal event, as the activity of HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis), assessed in vitro, was decreased following Mn-BR treatment. Treatment with the Mn-BR combination may affect other aspects of intracellular cholesterol dynamics.

Animals↗

PubMed1998

Constant-pressure molecular dynamics investigation of cholesterol effects in a dipalmitoylphosphatidylcholine bilayer.

We report a 1.4-ns constant-pressure molecular dynamics simulation of cholesterol at 12.5 mol% in a dipalmitoylphosphatidylcholine (DPPC) bilayer at 50 degrees C and compare the results to our previous simulation of a pure DPPC bilayer. The interlamellar spacing was increased by 2.5 A in the cholesterol-containing bilayer, consistent with x-ray diffraction results, whereas the bilayer thickness was increased by only 1 A. The bilayer/water interface was more abrupt because the lipid headgroups lie flatter to fill spaces left by the cholesterol molecules. This leads to less compensation by the lipid headgroups of the oriented water contribution to the membrane dipole potential and could explain the experimentally observed increase in the magnitude of the dipole potential by cholesterol. Our calculations suggested that 12.5 mol% cholesterol does not significantly affect the conformations and packing of the hydrocarbon chains and produces only a slight reduction in the empty free volume. However, cholesterol has a significant influence on the subnanosecond time scale lipid dynamics: the diffusion constant for the center-of-mass "rattling" motion was reduced by a factor of 3, and the reorientational motion of the methylene groups was slowed along the entire length of the hydrocarbon chains.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1980

A comparison of the turnover and metabolism cholesterol in normal and atherosclerotic monkey aortas.

Rhesus monkeys were fed high cholesterol and cholesterol-free diets for 21-24 months. The animals were then given isotopic cholesterol intravenously and autopsied from 1 to 51 weeks later. The plasma and aortic cholesterol contents were 633 +/- 130 mg/dl and 35.6 +/- 11.4 mg/g dried tissue (45.5% in ester form) for atherosclerotic monkeys and 135 +/- 25 mg/dl and 9.9 +/- 3.6 mg/g (15.0% in ester form) for control monkeys, respectively. The minimal influx rate of cholesterol from plasma into the aorta was much greater for atherosclerotic animals, 0.470 +/- 0.20 mg/g per day versus 0.088 +/- 0.031 for control monkeys. There was a rapid turnover of both free and esterified cholesterol in the atherosclerotic aortas, greater than for normal aortas. These studies of cholesteryl ester metabolism indicated a likely origin of aortic cholesteryl ester from the plasma cholesteryl esters. Our data indicated a dynamic cholesterol metabolism and turnover in the aorta during atherogenesis.

Animals↗

PubMed2001

Amyloid beta-peptide1-40 increases neuronal membrane fluidity: role of cholesterol and brain region.

There is increasing evidence of an interaction between cholesterol dynamics and Alzheimer's disease (AD), and amyloid beta-peptide may play an important role in this interaction. Abeta destabilizes brain membranes and this action of Abeta may be dependent on the amount of membrane cholesterol. We tested this hypothesis by examining effects of Abeta1-40 on the annular fluidity (i.e., lipid environment adjacent to proteins) and bulk fluidity of rat synaptic plasma membranes (SPM) of the cerebral cortex, cerebellum, and hippocampus using the fluorescent probe pyrene and energy transfer. Amounts of cholesterol and phospholipid of SPM from each brain region were determined. SPM of the cerebellum were significantly more fluid as compared with SPM of the cerebral cortex and hippocampus. Abeta significantly increased (P < or = 0.01) annular and bulk fluidity in SPM of cerebral cortex and hippocampus. In contrast, Abeta had no effect on annular fluidity and bulk fluidity of SPM of cerebellum. The amounts of cholesterol in SPM of cerebral cortex and hippocampus were significantly higher (P < or = 0.05) than amount of cholesterol in SPM of cerebellum. There was significantly less (P < or = 0.05) total phospholipid in cerebellar SPM as compared with SPM of cerebral cortex. Neuronal membranes enriched in cholesterol may promote accumulation of Abeta by hydrophobic interaction, and such an interpretation is consistent with recent studies showing that soluble Abeta can act as a seed for fibrillogenesis in the presence of cholesterol.

Amyloid beta-Peptides↗

PubMed1999

Anisotropic motion of cholesterol in oriented DPPC bilayers studied by quasielastic neutron scattering: the liquid-ordered phase.

Quasielastic neutron scattering (QENS) at two energy resolutions (1 and 14 microeV) was employed to study high-frequency cholesterol motion in the liquid ordered phase (lo-phase) of oriented multilayers of dipalmitoylphosphatidylcholine at three temperatures: T = 20 degrees C, T = 36 degrees C, and T = 50 degrees C. We studied two orientations of the bilayer stack with respect to the incident neutron beam. This and the two energy resolutions for each orientation allowed us to determine the cholesterol dynamics parallel to the normal of the membrane stack and in the plane of the membrane separately at two different time scales in the GHz range. We find a surprisingly high, model-independent motional anisotropy of cholesterol within the bilayer. The data analysis using explicit models of molecular motion suggests a superposition of two motions of cholesterol: an out-of-plane diffusion of the molecule parallel to the bilayer normal combined with a locally confined motion within the bilayer plane. The rather high amplitude of the out-of-plane diffusion observed at higher temperatures (T >/= 36 degrees C) strongly suggests that cholesterol can move between the opposite leaflets of the bilayer while it remains predominantly confined within its host monolayer at lower temperatures (T = 20 degrees C). The locally confined in-plane cholesterol motion is dominated by discrete, large-angle rotational jumps of the steroid body rather than a quasicontinous rotational diffusion by small angle jumps. We observe a significant increase of the rotational jump rate between T = 20 degrees C and T = 36 degrees C, whereas a further temperature increase to T = 50 degrees C leaves this rate essentially unchanged.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1996

Twenty-year dynamics of serum cholesterol levels in the middle-aged population of eastern Finland.

BACKGROUND: In cross-sectional analyses, serum cholesterol levels differ among different age groups. However, secular time trends in cholesterol levels can be seen across age groups in a population. A birth cohort analysis provides useful information on the combined effect of age and time on changes in serum cholesterol levels. OBJECTIVE: To analyze the 20-year dynamics of serum total cholesterol levels in relation to age, sex, birth cohort, time period, mortality rate, and changes in the intake of saturated fats. DESIGN: Cross-sectional measurements of serum total cholesterol levels in five independent population surveys done in 1972, 1977, 1982, 1987, and 1992. SETTING: Kuopio and North Karelia provinces in eastern Finland. PATIENTS: Random sample of 16,711 men and 17,542 women 25 to 64 years of age. Persons in the oldest birth cohort were born in 1913; persons in the youngest birth cohort were born in 1967. MEASUREMENTS: Total serum cholesterol levels and daily intake of dietary fat. RESULTS: Between 1972 and 1992, mean cholesterol levels decreased with time in each age group and for both sexes. According to the cross-sectional data, cholesterol levels increased with age and increased more steeply in women than in men. Contrary to these data, cholesterol levels in birth cohorts did not increase with age. Cholesterol levels did not change at all within birth cohorts of women and started to decrease after 45 years of age in birth cohorts of men. Cholesterol levels in the youngest birth cohorts (persons 25 to 29 years of age) entering the study each study year were markedly lower than levels in the same age group in the previous survey of risk factors. Daily intake of saturated fat decreased markedly between 1972 and 1992. Most of this decrease could be explained by change in intake of liquid dairy products and spreadable fats. In both sexes, changes in saturated fat intake were correlated with the time period, whereas the association with age was weak. CONCLUSIONS: In this Finnish population, total serum cholesterol levels are more closely associated with birth cohort than with age. Changes in dietary intake of saturated fat over time may account for changes in cholesterol levels. This finding suggests that community-based strategies for preventing cardiovascular disease can affect most of the population.

Adult↗

PubMed2004

Cholesterol homeostasis failure as a unifying cause of synaptic degeneration.

We previously showed that fine tuning of neural cholesterol dynamics is essential for basic synapse function, plasticity and behavior. Significant experimental evidence indicates that cholinergic function, ionotropic and metabotropic receptor machinery, excessive tau phosphorylation, the change of amyloid beta (Abeta or Abeta) biochemistry, neural oxidative stress reactions, and other features of neurodegeneration also depend on fine tuning of brain cholesterol homeostasis. This evidence suggest that (i) cholesterol homeostasis break is the unifying primary cause of sporadic and familial Alzheimer's disease (AD), neuromuscular diseases (particularly inclusion-body myositis), Niemann-Pick's type C disease and Down syndrome, and (ii) explains the overlap of neurodegenerative hallmarks across the spectrum of neurodegenerative diseases. Provided is evidence-based explanation of why extremely rare (but scientifically popular) cases of AD associated with mutations in amyloid beta protein precursor (APP) and presenilin (PS) genes, are translated into the disorder via membrane cholesterol sensitivity of APP processing by secretases and Abeta generation. The reciprocal effect of Abeta on cholesterol synthesis, cellular uptake, efflux and esterification is summarized, as well as the potential implication of such biological function for the compensatory Abeta-assisted restoration of the synaptic long-term potentiation (LTP) and resulting inability of tackling amyloid to cure AD.

Alzheimer Disease↗

PubMed1981

Dissolution rate behavior of solid cholesterol preparations in bile acid solutions.

Recent work in these laboratories showed that different preparations of cholesterol monohydrate and anhydrous cholesterol had different dissolution rates under the same conditions. A method was developed by which both the thermodynamic contribution (Cs) and the interfacial kinetic contribution (P) to dissolution could be determined from experimental data. The rotating-disk dissolution method was used with the Levich theory to assess the data. Dissolution rates were determined in solutions partially saturated with cholesterol. Dynamic solubilities were determined by plotting dissolution rates (J/A) versus bulk concentration (Cb) and extrapolating to zero J/A. By using a best-fit analysis, it was possible to determine solubility as well as the interfacial transport constant independently. When this method was used to study differences in dissolution behavior of different solid preparations of cholesterol the differences could be accounted for primarily by variations in the interfacial transport constant rather than by solubility variations.

Benzoates↗