RESUMEN
Epicatechin is a widely consumed dietary flavonoid and there is substantial evidence that it contributes to the health benefits reported for flavanol-rich cocoa products including dark chocolate. Numerous reports have described the appearance of epicatechin and epicatechin phase-2 conjugates (sulfates and glucuronides of epicatechin and methylepicatechin) in blood and urine samples of subjects following ingestion of epicatechin. The most widely reported method of quantifying total epicatechin in plasma and urine samples involves hydrolysis with a mixture of ß-glucuronidase and sulfatase to convert the conjugates to epicatechin aglycone which is subsequently quantified. We observed a lack of hydrolysis of epicatechin sulfates and methylepicatechin sulfates using commercial sulfatases and investigated this further. Samples of urine or plasma from subjects who had consumed epicatechin were subjected to enzyme hydrolysis and then analysed using LC-MS/MS, or analysed without enzyme hydrolysis. Attempts to increase the extent of hydrolysis of epicatechin conjugates were made by increasing the amount of enzyme, hydrolysis pH and length of incubations, and using alternative sources of enzyme. The standard hydrolysis conditions failed to hydrolyse the majority of epicatechin sulfates and methylepicatechin sulfates. Even when the quantity of enzyme and incubation period was increased, the pH optimised, or alternative sources of sulfatases were used, epicatechin monosulfates and methylepicatechin monosulfates remained as major peaks in the chromatograms of the samples. An assessment of literature data strongly suggested that the majority of reports where enzyme hydrolysis was used had significantly underestimated epicatechin bioavailability in humans. Methods for quantifying epicatechin concentrations in blood and urine need to take account of the lack of hydrolysis of (methyl)epicatechin-sulfates, for example by quantifying these directly using LC-MS/MS.
Asunto(s)
Arilsulfatasas/metabolismo , Catequina/análogos & derivados , Ésteres del Ácido Sulfúrico/metabolismo , Administración Oral , Disponibilidad Biológica , Biotransformación , Catequina/administración & dosificación , Catequina/sangre , Catequina/metabolismo , Catequina/orina , Cromatografía Liquida , Estudios Cruzados , Inglaterra , Femenino , Glucuronidasa/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Masculino , Metilación , Reproducibilidad de los Resultados , Especificidad por Sustrato , Ésteres del Ácido Sulfúrico/administración & dosificación , Ésteres del Ácido Sulfúrico/sangre , Ésteres del Ácido Sulfúrico/orina , Espectrometría de Masas en Tándem , Factores de TiempoRESUMEN
Conjugated linoleic acids (CLA) affect atherogenesis, but mechanisms are not well understood. We explored how two isomers of CLA, cis9, trans11-CLA and trans10, cis12-CLA, affected lipid and glucose metabolism, as well as hepatic protein expression, in apolipoprotein E knockout mice. After 12 wk of intervention, plasma triglyceride, NEFA, and glucose concentrations were significantly higher in the trans10, cis12-CLA group, whereas plasma triglyceride, NEFA, glucose, and insulin concentrations were significantly lower in the cis9, trans11-CLA group, compared with control mice consuming linoleic acid. Proteomics identified significant up- or down-regulation of 113 liver cytosolic proteins by either CLA isomer. Principal component analysis revealed that the treatment effect of cis9, trans11-CLA was mainly explained by the up-regulation of different posttranslational forms of heat shock protein 70 kD. In contrast, the treatment effect of trans10, cis12-CLA was mainly explained by up-regulation of key enzymes in the gluconeogenic, beta-oxidation, and ketogenesic pathways. Correlation analysis again emphasized the divergent effects of both CLA isomers on different pathways, but also revealed a linkage between insulin resistance and increased levels of hepatic serotransferrin. Thus, our systems biology approach provided novel insights into the mechanisms by which individual CLA isomers differentially affect pathways related to atherogenesis, such as insulin resistance and inflammation.
Asunto(s)
Apolipoproteínas E/genética , Ácido Linoleico/química , Ácidos Linoleicos Conjugados/metabolismo , Proteómica/métodos , Alimentación Animal , Animales , Aterosclerosis/patología , Glucemia/metabolismo , Western Blotting , Composición Corporal , Peso Corporal , Citosol/metabolismo , Dieta , Ácidos Grasos/metabolismo , Ligamiento Genético , Glucosa/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Inflamación , Insulina/metabolismo , Resistencia a la Insulina , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Oxígeno/metabolismo , Perfusión , Análisis de Componente Principal , Biología de Sistemas , Triglicéridos/metabolismoRESUMEN
BACKGROUND: Cafestol is a diterpene in unfiltered coffee that raises plasma triacylglycerol in humans. OBJECTIVE: We studied whether cafestol increases plasma triacylglycerol by increasing the production rate or by decreasing the fractional catabolic rate of VLDL(1) [Svedberg flotation unit (S(f)) 60-400] apolipoprotein (apo) B. In addition, we studied the effect of cafestol on the composition of VLDL(1) and VLDL(2) (S(f) 20-60). DESIGN: Eight healthy normolipidemic men were administered a daily dose of 75 mg cafestol for 2 wk. A bolus injection of 7 mg L-[5,5,5-(2)H(3)]leucine/kg body wt was given after a baseline period with no cafestol and again after treatment with cafestol. We derived kinetic constants to describe the metabolism of VLDL(1) apo B by using a multicompartmental model. RESULTS: Cafestol significantly increased plasma triacylglycerol by 31% or 0.32 mmol/L (95% CI: 0.03, 0.61); the increase was due mainly to a nonsignificant rise in VLDL(1) triacylglycerol of 57% or 0.23 mmol/L (95% CI: -0.02, 0.48). Cafestol significantly increased the mean rate of VLDL(1) apo B production by 80% or 755 mg/d (95% CI: 0.2, 5353), whereas it did not significantly change the mean fractional catabolic rate of VLDL(1) apo B (mean increase of 3 pools/d; 95% CI: -4, 10]). Cafestol did not change the composition of VLDL(1). A significant increase in the ratio of VLDL(2) cholesteryl ester to triacylglycerol indicates that VLDL(2) became enriched with cholesteryl esters at the cost of triacylglycerol. CONCLUSION: Cafestol increases plasma triacylglycerol by increasing the production rate of VLDL(1) apo B, probably via increased assembly of VLDL(1) in the liver.
Asunto(s)
Apolipoproteínas B/biosíntesis , Café/química , Diterpenos/farmacología , Lipoproteínas VLDL/biosíntesis , Triglicéridos/sangre , Adulto , Alanina Transaminasa/sangre , Apolipoproteínas B/metabolismo , Humanos , Metabolismo de los Lípidos , Lípidos/farmacocinética , Lipoproteínas VLDL/química , Lipoproteínas VLDL/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Modelos Biológicos , Factores de TiempoRESUMEN
The St. Thomas mixed hyperlipidaemic (SMHL) rabbit exhibits an inherited hyperlipidaemia similar to that seen in familial combined hyperlipidaemia (FCHL). In this study, we investigated whether the SMHL rabbit is insulin resistant, a condition often associated with FCHL. Six young and six mature combined hyperlipidaemic SMHL rabbits, age/sex matched New Zealand White (NZW) control rabbits and six young hypercholesterolaemic Watanabe heritable hyperlipidaemic (WHHL) control rabbits were fed a 0.08% (w/w) cholesterol-enriched diet for at least 1 month prior to the start of the experiment. We performed an oral glucose tolerance test after an overnight fast by dosing the rabbits with a solution of 1 g of glucose per kg body weight. Blood was withdrawn just before and 15, 30, 45, 60 and 120 min after administration of the oral glucose dose. Plasma glucose levels were similar in SMHL, WHHL and NZW rabbits throughout the oral glucose tolerance test. Fasting glucose levels were slightly increased in WHHL rabbits but not in young and adult SMHL rabbits as compared to NZW rabbits. The area under the curve (AUC) for the insulin response was significantly increased for both young (P<0.05) and mature (P<0.05) SMHL rabbits, and in WHHL rabbits, compared with NZW rabbits. The AUC for the ratio of glucose:insulin response to the glucose dose was decreased in young and mature SMHL rabbits (P<0.05 and P<0.01, respectively) and in young WHHL rabbits (P<0.05), compared with NZW rabbits. Only WHHL rabbits showed an increased AUC for the non-esterified fatty acid response compared to NZW rabbits. Log-transformed plasma triglycerides values were significantly correlated with the log-transformed AUC for the insulin response in young SMHL rabbits (r=0.81; P<0.05) and with the AUC for the insulin response in mature SMHL rabbits (r=0.84; P<0.05). WHHL rabbits showed no significant correlation. In conclusion, SMHL rabbits are insulin resistant, the severity of which appears to increase with age. Therefore, the SMHL rabbit offers a valuable animal model in which to study the relation between hypertriglyceridaemia and insulin resistance.
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Glucemia/metabolismo , Hiperinsulinismo/fisiopatología , Hiperlipidemia Familiar Combinada/fisiopatología , Hipertrigliceridemia/fisiopatología , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Animales , Área Bajo la Curva , Colesterol en la Dieta/administración & dosificación , Colesterol en la Dieta/metabolismo , Modelos Animales de Enfermedad , Prueba de Tolerancia a la Glucosa , Hiperinsulinismo/complicaciones , Hiperlipidemia Familiar Combinada/complicaciones , Hipertrigliceridemia/complicaciones , Insulina/farmacocinética , Masculino , Probabilidad , Conejos , Radioinmunoensayo , Valores de Referencia , Medición de Riesgo , Sensibilidad y EspecificidadRESUMEN
Cafestol and kahweol-diterpenes present in unfiltered coffee-strongly raise serum VLDL and LDL cholesterol and slightly reduce HDL cholesterol in humans. The mechanism of action is unknown. We determined whether the coffee diterpenes may affect lipoprotein metabolism via effects on lipid transfer proteins and lecithin:cholesterol acyltransferase in a randomized, double-blind cross-over study with 10 healthy male volunteers. Either cafestol (61-64 mg/day) or a mixture of cafestol (60 mg/day) and kahweol (48-54 mg/day) was given for 28 days. Serum activity levels of cholesterylester transfer protein, phospholipid transfer protein and lecithin:cholesterol acyltransferase were measured using exogenous substrate assays. Relative to baseline values, cafestol raised the mean (+/- S.D.) activity of cholesterylester transfer protein by 18 +/- 12% and of phospholipid transfer protein by 21 +/- 14% (both P < 0.001). Relative to cafestol alone, kahweol had no significant additional effects Lecithin:cholesterol acyltransferase activity was reduced by 11 +/- 12% by cafestol plus kahweol (P = 0.02). It is concluded that the effects of coffee diterpenes on plasma lipoproteins may be connected with changes in serum activity levels of lipid transfer proteins.
Asunto(s)
Proteínas Portadoras/sangre , Diterpenos/administración & dosificación , Adulto , Café/efectos adversos , Humanos , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , MasculinoRESUMEN
The usefulness of fluorescence in situ hybridization (FISH) with rat satellite I DNA was compared with immunocytochemical staining with CREST serum for the analysis of the content of micronuclei from primary rat fibroblasts. We analyzed micronuclei induced in vitro by the aneugenic compound diethylstilbestrol (DES) or the clastogenic compound mitomycin C (MMC). Since a centromeric probe was not available for the rat, we isolated rat satellite I DNA by PCR with primers designed on the basis of the known rat satellite I DNA sequence. The PCR products obtained as well as the cloned PCR products showed hybridization to the centromeric regions of a large number of chromosomes, but not of chromosome 1, 19, 20, X and Y. Clone 18-5 was further analyzed and was shown to contain at least 4 repeats of the rat satellite I family. This probe, which hybridizes in the centromeric region of 34 of the 42 chromosomes, was used throughout the study as a probe for the FISH analysis of the micronuclei. For the immunocytochemical staining, the commonly used commercial anti-centromeric antibodies could not be used because of the weakness of the fluorescent signals given. Consequently, CREST serum of a single patient was used, which showed bright and distinct signals on the kinetochores of each chromosome. After treatment of the cells with the aneugen DES an increase in centromere (FISH) and kinetochore (CREST) positive micronuclei was found, whereas after treatment with the clastogen MMC, the percentage of centromere-positive micronuclei was similar to that observed in controls. Analysis of a large number of DES-induced micronuclei showed that the immunocytochemical method is equally as or slightly less sensitive for the detection of chromosomes in micronuclei and we therefore recommend FISH with probe 18-5 for the detection of chromosome loss in rat cells.
Asunto(s)
Sondas de ADN , Técnica del Anticuerpo Fluorescente Indirecta/métodos , Hibridación Fluorescente in Situ/métodos , Pruebas de Micronúcleos/métodos , Animales , Autoanticuerpos , Síndrome CREST/inmunología , Células Cultivadas , Centrómero/genética , ADN Satélite , Dietilestilbestrol , Fibroblastos , Humanos , Masculino , Mitomicina , Mutágenos , Ratas , Ratas WistarRESUMEN
Fourteen infants of 2 months or 6 months of age were video-recorded during polysomnography. Four were normal infants, five had a history of ALTE (apparent life threatening event) and five had repeated and prolonged apnoea during sleep. Two ALTE infants have been recorded at 2 months as well as at 6 months of age. Movements during sleep could be classified into general movements, isolated movements of the upper extremity, startles, head rotations, and trunk rotations. In the ALTE cases at 2 months of age, the motility was quantitatively not different from the control infants but was markedly reduced at 6 months of age. (All cases had their event before 8 weeks of age.) In contrast to these findings, infants with repeated apnoea did not show a clear change in the quantity of their movements. With the exception of one ALTE case at 2 months, all observed cases of ALTE and apnoeic infants showed an abnormal quality of their spontaneous movements during sleep. As reported in a previous study, all these cases had also been found moving abnormally during wakefulness. It is suggested that the abnormal motility is a sequelae of the event (ALTE or repeated apnoeas) with as a consequence, an impairment of neural functions.
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Movimiento , Síndromes de la Apnea del Sueño/fisiopatología , Envejecimiento , Electrocardiografía , Electroencefalografía , Electromiografía , Electrooculografía , Frecuencia Cardíaca , Humanos , Lactante , Proyectos Piloto , Respiración , Sueño/fisiología , Sueño REM/fisiología , Grabación en VideoRESUMEN
Inhibition of intercellular communication (IC) between hepa1c1c7 cells was used as a possible bioassay to predict tumor promoting potency of polyhalogenated aromatic hydrocarbons (PAHs). Relative potencies with regard to 2,3,7,8-TCDD to inhibit IC and to induce cytochrome P450IA1/2 (EROD) in these hepa1c1c7 cells were compared in order to investigate the possible role of the Ah receptor (AhR). For the PCDD/F and the co-planar PCB congeners relative potencies of both responses were within the same range. However, the mono-ortho PCBs, 2,3,3',4,4'-PeCB, 2,3,4,4',5-PeCB, 2,3',4,4',5-PeCB and 2,3,3',4,4',5,5'-HxCB showed a 30-1300 times higher potency to inhibit IC compared to EROD induction activity. These potency differences were even more pronounced for the di-ortho PCBs, 2,2',5,5'-TeCB and 2,2',3,3',4,4'-HxCB. The data presented here indicate that for IC inhibition by these non-planar PCBs a non-AhR mediated mechanism, with a different structure-activity relationship may be responsible. Given the high IC inhibition potency of mono- and di-ortho PCBs and their abundancy in environmental mixtures, the mono- and di-ortho PCBs may contribute for a major part to the total tumor promoting potency of complex mixtures relevant to human exposure. Using the traditional TEF values, these compounds do not account for much toxic potency in a mixture, which may imply that the tumor promotion potential is not covered by the commonly derived TEF values.
RESUMEN
Activated platelets contribute to plaque formation within blood vessels in the early and late stages of atherogenesis, and therefore they have been proposed as risk factor for cardiovascular disease. Anti-platelet drugs, such as aspirin, are now the most prescribed pharmacological treatment in Europe. Certain dietary bioactives also beneficially affect platelet function, and with less side effects, albeit that effects are generally more subtle. Therefore, consumption of dietary bioactives could play a role in the prevention of atherothrombotic vascular disease. Here we review the efficacy of dietary treatment strategies, especially those involving certain dietary fatty acids and polyphenols, to modulate platelet function in healthy subjects or in patients with cardiovascular disease. Variation in study populations, small study sizes and lack of comparability between methods to assess platelet function currently limit robust evidence on the efficacy of dietary bioactives in healthy subjects or specific patient groups. Also, limited knowledge of the metabolism of dietary bioactives, and therefore of the bioavailability of bioactive ingredients, restricts our ability to identify the most effective dietary regimes to improve platelet function. Implementation of uniform point-of-care tests to assess platelet function, and enhanced knowledge of the efficacy by which specific dietary compounds and their metabolites affect platelet function, may enable the identification of functional anti-platelet ingredients that are eligible for a health claim, or combined treatment strategies, including both pharmacological anti-platelet treatment as well as dietary intervention, to tackle atherothrombotic vascular disease.
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Plaquetas/metabolismo , Dieta , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Aterosclerosis/fisiopatología , Flavonoides/farmacología , Humanos , Inflamación/fisiopatología , Placa Aterosclerótica/fisiopatología , Activación Plaquetaria/fisiología , Pruebas de Función Plaquetaria , Polifenoles/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Factores SexualesRESUMEN
There is growing interest in the potential health benefits of diets that involve regular periods of fasting. While animal studies have provided compelling evidence that feeding patterns such as alternate-day fasting can increase longevity and reduce incidence of many chronic diseases, the evidence from human studies is much more limited and equivocal. Additionally, although several candidate processes have been proposed to contribute to the health benefits observed in animals, the precise molecular mechanisms responsible remain to be elucidated. The study described here examined the effects of an extended fast on gene transcript profiles in peripheral blood mononuclear cells from ten apparently healthy subjects, comparing transcript profiles after an overnight fast, sampled on four occasions at weekly intervals, with those observed on a single occasion after a further 24 h of fasting. Analysis of the overnight fasted data revealed marked inter-individual differences, some of which were associated with parameters such as gender and subject body mass. For example, a striking positive association between body mass index and the expression of genes regulated by type 1 interferon was observed. Relatively subtle changes were observed following the extended fast. Nonetheless, the pattern of changes was consistent with stimulation of fatty acid oxidation, alterations in cell cycling and apoptosis and decreased expression of key pro-inflammatory genes. Stimulation of fatty acid oxidation is an expected response, most likely in all tissues, to fasting. The other processes highlighted provide indications of potential mechanisms that could contribute to the putative beneficial effects of intermittent fasting in humans.
RESUMEN
Whole-grain diets are linked to reduced risk of several chronic diseases (heart disease, cancer, diabetes, metabolic syndrome) and all-cause mortality. There is increasing evidence that these benefits are associated with the gut microbiota and that release of fibre-related phenolic metabolites in the gut is a contributing factor. Additional sources of these metabolites include fruits and vegetables, but the evidence for their protective effects is less well established. With respect to the availability of bound phytophenols, ready-to-eat cereals are compared with soft fruits (considered rich in antioxidants) and other commonly consumed fruits and vegetables. The results demonstrated that when compared with an equivalent serving of fruits or vegetables, a recommended portion of whole-grain cereals deliver substantially higher amounts of bound phytophenols, which are available for metabolism in the colon. The increased amount of these phenolic metabolites may, in part, explain the evidence for the protective effects of whole-grain cereals.
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Grano Comestible/química , Comida Rápida/análisis , Frutas/química , Fenol/química , Extractos Vegetales/química , Verduras/química , Antioxidantes/química , Antioxidantes/metabolismo , Fibras de la Dieta/análisis , Fibras de la Dieta/metabolismo , Grano Comestible/metabolismo , Frutas/metabolismo , Humanos , Fenol/metabolismo , Extractos Vegetales/metabolismo , Verduras/metabolismoRESUMEN
Cafestol, a coffee diterpene present in unfiltered coffee brews, potently raises serum lipids in humans. The mechanism through which this dietary compound influences liporotein metabolism is largely unknown. Unravelling the mechanism of action might lead to new insights into the regulation of serum cholesterol levels in humans. This review summaries ways in which cafestol may act on serum lipids.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT , Colesterol/sangre , Café/química , Diterpenos/farmacología , Glicoproteínas , Proteínas Portadoras/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol , Proteínas de Unión al ADN/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Factores de Transcripción/metabolismoRESUMEN
Cafestol and kahweol, coffee lipids present in unfiltered coffee brews, potently increase LDL-cholesterol concentration in human subjects. We searched for an animal species in which cafestol similarly increases LDL-cholesterol. Such an animal model could be used subsequently as a model to study the mechanism of action of cafestol and kahweol. Cafestol and kahweol increased serum lipids in African green monkeys (Cercopithecus aethiops), cebus (Cebus apella) and rhesus (Macaca mulatta) monkeys, hamsters, rats and gerbils differently from the increase in human subjects. In African green monkeys, the rise in total cholesterol was less pronounced than that in human subjects. In addition, the increase in total cholesterol was predominantly due to a rise in HDL-cholesterol rather than LDL-cholesterol. Thus, the rise in plasma lipids might illustrate the mechanism in these monkeys rather than the mechanism in human subjects. In other animal species, cafestol and kahweol did not raise cholesterol consistently. The variability in effects on serum lipids could not be explained by the mode of administration or dose of diterpenes, nor by the amount of cholesterol in the diet. In conclusion, we did not find an animal model in which cafestol and kahweol elevate plasma lipoproteins to the same extent as in human subjects. For the time being, therefore, studies on the mechanism of action should be done preferably in human subjects.
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Colesterol/sangre , Café/química , Diterpenos/farmacología , Modelos Biológicos , Animales , Chlorocebus aethiops , Humanos , Lípidos/sangreRESUMEN
Behaviour can, in general, not be quantified on an equal-interval scale; therefore, the description of sequential aspects of the behaviour of two interacting individuals can not be formulated on the basis of the usual cross-correlation techniques. If the information content of behaviour, however, is defined analogously to the entropy in a message, this allows a quantification of the contribution of either participant to the interaction process, and the identification of a non-additive (synergic) component in addition to the auto- and cross-covariability terms. Such a framework, based on the concept of transinformation or mutual information, was developed and realised in a suite of three FORTRAN programs. These were then applied in a longitudinal study on the development of early mother-infant interaction. The synergic term appears to increase with age in the first five months of life. This application illustrates the usefulness of information statistics for quantifying the ways in which participants contribute to a process of interaction.
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Teoría de la Información , Relaciones Madre-Hijo , Interpretación Estadística de Datos , Femenino , Humanos , Lactante , Recién Nacido , Modelos Psicológicos , Programas InformáticosRESUMEN
OBJECTIVES: To determine the absorption and urinary excretion of the cholesterol-raising coffee diterpenes cafestol and kahweol in humans. SUBJECTS AND DESIGN: Nine healthy ileostomists consumed a dose of one, two or three cups of French-press coffee together with a standardized breakfast on three separate days in random order. Subsequently, ileostomy effluent was collected for 14 h and urine for 24 h. Stability of cafestol and kahweol was also assessed under simulated gastrointestinal tract conditions. MAIN OUTCOME MEASURES: Absorption of diterpenes, stability of diterpenes during incubation with gastrointestinal fluids, and urinary excretion of diterpenes. RESULTS: Corrected mean absorptions expressed as percentages of the amount consumed and the amount entering the duodenum were 67 and 88%, respectively, for cafestol, and 72 and 93%, respectively, for kahweol. We found losses of diterpenes during incubation in vitro with gastric juice (cafestol, 24%; kahweol, 32%), during storage with ileostomy effluent (cafestol, 18%; kahweol, 12%), and during freeze-drying (cafestol, 26%; kahweol, 32%). Mean excretion of glucuronidated plus sulphated conjugates in urine was 1.2% of the ingested amount for cafestol and 0.4% of the ingested amount for kahweol. CONCLUSIONS: About 70% of the ingested cafestol and kahweol is absorbed in ileostomy volunteers. Possibly, undetected metabolites are present in ileostomy effluent, resulting in lower absorption percentages. Only a small part of the diterpenes is excreted as a conjugate of glucuronic acid or sulphate in urine. Therefore, these compounds are extensively metabolized in the human body.
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Diterpenos/farmacocinética , Ileostomía , Absorción Intestinal/fisiología , Adulto , Anciano , Café/metabolismo , Diterpenos/orina , Estabilidad de Medicamentos , Duodeno/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Distribución AleatoriaRESUMEN
Boiled coffee contains the lipid compounds cafestol and kahweol, which raise cholesterol strongly in man. These lipids are retained by paper filters. In a search for an animal model for the effect of coffee lipids on serum cholesterol concentrations, we fed hamsters (Mesocricetus auratus) and rats on mash diets consisting of a purified base diet and either boiled water, unfiltered boiled coffee or filtered boiled coffee. After a feeding period of 8 weeks there was no statistically significant effect of unfiltered boiled coffee on serum total cholesterol and triacylglycerol concentrations in either the hamsters or the rats. The level of serum cholesterol did respond predictably to the addition of cholesterol and/or saturated fatty acids to the diet. The lack of effect of unfiltered boiled coffee in the hamsters and the rats, when compared with the previously reported activity in humans, could not be explained by dosage, duration of treatment, mode of administration or by insufficient statistical power. It is concluded that hamsters and rats are insensitive to unfiltered boiled coffee and thus are unsuitable models for investigating its hypercholesterolaemic effect.
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Colesterol/metabolismo , Café/efectos adversos , Modelos Animales de Enfermedad , Hipercolesterolemia/metabolismo , Animales , Cricetinae , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Mesocricetus , Ratas , Ratas WistarRESUMEN
OBJECTIVES: To determine the long-term effects of unfiltered coffee consumption on the activity levels of cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP) and lecithin:cholesterol acyltransferase (LCAT) and to assess a possible role of CETP activity levels in the rise in serum LDL cholesterol. SUBJECTS AND DESIGN: Forty-six healthy normolipidaemic subjects consumed 0.9 L of either French-press or filtered coffee for 24 weeks. Fasting blood samples were obtained after 0, 2, 12 and 24 weeks of intervention and after and 12 weeks of follow-up. MAIN OUTCOME MEASURES: Serum activity levels of CETP, PLTP and LCAT. RESULTS: Relative to baseline, French-press coffee significantly increased average CETP activity by 12% after 2 weeks, by 18% after 12 weeks, and by 9% after 24 weeks. PLTP activity was significantly increased by 10% after 12 and 24 weeks. LCAT activity was significantly decreased by 6% after 12 weeks and by 7% after 24 weeks. The increase in CETP clearly preceded the increase in LDL cholesterol, but not the increase in total triglycerides. However, consumption of French-press coffee caused a persistent rise in CETP activity, whereas the rise in serum triglycerides was transient. CONCLUSIONS: Consumption of cafestol and kahweol cause a long-term increase in CETP as well as PLTP activity; the increase in CETP activity may contribute to the rise in LDL cholesterol.
Asunto(s)
Proteínas Portadoras/sangre , LDL-Colesterol/sangre , Diterpenos/efectos adversos , Glicoproteínas , Proteínas de Transferencia de Fosfolípidos , Adulto , Anciano , Proteínas de Transferencia de Ésteres de Colesterol , Café/efectos adversos , Femenino , Humanos , Masculino , Proteínas de la Membrana/sangre , Persona de Mediana Edad , Fosfatidilcolina-Esterol O-Aciltransferasa/sangreRESUMEN
Cafestol, a diterpene present in unfiltered coffee, potently increases serum cholesterol levels in humans. So far, no suitable animal model has been found to study the biochemical background of this effect. We determined the effect of cafestol on serum cholesterol and triglycerides in different mouse strains and subsequently studied its mechanism of action in apolipoprotein (apo) E*3-Leiden transgenic mice. ApoE*3-Leiden, heterozygous low density lipoprotein-receptor (LDLR+/-) knockout, or wild-type (WT) C57BL/6 mice were fed a high- (0.05% wt/wt) or a low- (0.01% wt/wt) cafestol diet or a placebo diet for 8 weeks. Standardized to energy intake, these amounts are equal to 40, 8, or 0 cups of unfiltered coffee per 10 MJ per day in humans. In apoE*3-Leiden mice, serum cholesterol was statistically significantly increased by 33% on the low- and by 61% on the high-cafestol diet. In LDLR+/- and WT mice, the increases were 20% and 24%, respectively, on the low-cafestol diet and 55% and 46%, respectively, on the high-cafestol diet. These increases were mainly due to a rise in very low density lipoprotein (VLDL) and intermediate density lipoprotein cholesterol in all 3 mouse strains. To investigate the mechanism of this effect, apoE*3-Leiden mice were fed a high-cafestol or a placebo diet for 3 weeks. Cafestol suppressed enzyme activity and mRNA levels of cholesterol 7alpha-hydroxylase by 57% and 58%, respectively. mRNA levels of enzymes involved in the alternate pathway of bile acid synthesis, ie, sterol 27-hydroxylase and oxysterol 7alpha-hydroxylase, were reduced by 32% and 48%, respectively. The total fecal bile acid output was decreased by 41%. Cafestol did not affect hepatic free and esterified cholesterol, but it decreased LDLR mRNA levels by 37%. The VLDL apoB and triglyceride production rates, as measured after Triton injection, were 2-fold decreased by cafestol, indicating that the number of particles secreted had declined and that there was no change in the amount of triglycerides present in the VLDL particle during cafestol treatment. However, the VLDL particles contained a 4-times higher amount of cholesteryl esters, resulting in a net 2-fold increased secretion of cholesteryl esters. The decrease in triglyceride production was the result of a reduction in hepatic triglyceride content by 52%. In conclusion, cafestol increases serum cholesterol levels in apoE*3-Leiden mice by suppression of the major regulatory enzymes in the bile acid synthesis pathways, leading to decreased LDLR mRNA levels and increased secretion of hepatic cholesterol esters. We suggest that suppression of bile acid synthesis may provide an explanation for the cholesterol-raising effect of cafestol in humans.