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Evidence for a protective role of the glutathione biotransformation system in carcinogenesis is growing. However, most data on this system in relation to colorectal cancer originate from animal studies. Here we review the human data. In humans, a significant association was found between glutathione S-transferase (GST) activity in the mucosa along the gastrointestinal tract and the corresponding tumour incidence. Low activity was correlated with high tumour incidence and vice versa. Also, in normal colonic mucosa, GST activity is lower in patients at risk of colon cancer than in healthy controls and therefore interventions which increase the glutathione detoxification capacity may reduce cancer incidence. Consumption of vegetables and fruit is associated with a lower risk of colorectal cancer. Human intervention studies showed that (components from) vegetables induced colonic glutathione detoxification capacity. Such an effect could contribute to a lower colon cancer risk, but further data are needed. The human GSTs consist of four main classes--alpha (A), mu (M), pi (P) and theta (T)--each of which is divided into one or more isoforms. Functional polymorphisms are known for the GST genes M1, P1 and T1 and they all lead to less active enzymes compared to the wild-type gene products. However, studies that compared these GST polymorphisms in relation to colon cancer risk were not conclusive with respect to an increased or decreased risk of a particular genotype. Diet or medication can also influence the expression levels of specific isoenzymes and the effect of such interventions on cancer risk deserves more attention.

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.

Background: Intake of unsaponifiable compounds from edible oils, such as plant sterols, can lower serum cholesterol concentrations in humans. However, little is known about effects of other chemically related unsaponifiables in edible oils, such as triterpene alcohols., Objective: We studied the effects of plant sterols from rice bran oil and triterpene alcohols from sheanut oil on cholesterol concentrations in healthy, normolipemic volunteers., Design: Twenty-eight men and 32 women consumed 29 g/d of 3 margarines for 3 wk each on a crossover, double-blind basis. A margarine based on sunflower oil was used as the control. Concentrates of plant sterols from rice bran oil or triterpene alcohols from sheanut oil were added to make 2 experimental margarines with the same fatty acid composition as the control margarine., Results: Intake of 2.1 g plant sterols/d from rice bran oil decreased total cholesterol by 0.19 mmol/L (95% CI: -0.31, -0.07 mmol/L) and LDL cholesterol by 0.20 mmol/L (95% CI: -0.30, -0.10 mmol/L). HDL-cholesterol and triacylglycerol concentrations did not change significantly. Intake of 2.6 g triterpene alcohols/d from sheanut oil did not significantly affect lipoprotein concentrations in all subjects combined., Conclusions: We found that 2.1 g plant sterols/d from rice bran oil lowered serum total cholesterol by 5% and LDL cholesterol by 9% in normolipemic humans, whereas triterpene alcohols from sheanut oil did not significantly affect lipoprotein concentrations in all subjects combined. The effect of rice bran oil sterols is probably due to ss-sitosterol and other 4-desmethylsterols and not to 4,4'-dimethylsterols.

Background: An elevated plasma concentration of total homocysteine is considered to be a strong risk factor for cardiovascular disease. Heavy coffee drinking has been related to high homocysteine concentrations in epidemiologic studies and in one experiment in which healthy subjects drank unfiltered, boiled coffee., Objective: Our goal was to determine whether daily consumption of paper-filtered coffee raises plasma concentrations of total homocysteine in healthy subjects., Design: Twenty-six volunteers (18-53 y of age) consumed 1 L/d of paper-filtered coffee brewed with 70 g regular ground beans or no coffee for 4 wk each in a randomized, crossover design., Results: The mean (+/-SD) plasma concentration of total homocysteine in fasting blood was 8.1 +/- 1.8 micromol/L after abstention from coffee and 9.6 +/- 2.9 micromol/L after 3-4 wk of coffee drinking, a difference of 1.5 micromol/L (95% CI: 0.9, 2.1 micromol/L) or 18% (P: < 0.001). Coffee increased homocysteine concentrations in 24 of 26 individuals. Circulating concentrations of vitamin B-6, vitamin B-12, and folate were unaffected., Conclusion: Drinking large quantities of paper-filtered coffee raises fasting plasma concentrations of total homocysteine in healthy individuals.

The response of serum lipids to dietary changes is to some extent an innate characteristic. One candidate genetic factor that may affect the response of serum lipids to a change in cholesterol intake is variation in the apolipoprotein A4 gene, known as the APOA4-1/2 or apoA-IVGln360His polymorphism. However, previous studies showed inconsistent results. We therefore fed 10 men and 23 women with the APOA4-1/1 genotype and 4 men and 13 women with the APOA4-1/2 or -2/2 genotype (carriers of the APOA4-2 allele) two diets high in saturated fat, one containing cholesterol at 12.4 mg/MJ, 136.4 mg/day, and one containing cholesterol at 86.2 mg/MJ, 948.2 mg/day. Each diet was supplied for 29 days in crossover design. The mean response of serum low density lipoprotein cholesterol was 0.44 mmol/l (17 mg/dl) in both subjects with the APOA4-1/1 genotype and in subjects with the APOA4-2 allele [95% confidence interval of difference in response, -0.20 to 0.19 mmol/l (-8 to 7 mg/dl)]. The mean response of high density lipoprotein cholesterol was also similar, 0.10 mmol/l (4 mg/dl), in the two APOA-4 genotype groups [95% confidence interval of difference in response, -0.07 to 0.08 mmol/l (-3 to 3 mg/dl)]. Thus, the APOA4-1/2 polymorphism did not affect the response of serum lipids to a change in the intake of cholesterol in this group of healthy Dutch subjects who consumed a background diet high in saturated fat. Knowledge of the APOA4-1/2 polymorphism is probably not a generally applicable tool for the identification of subjects who respond to a change in cholesterol intake.

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.

Background: Epidemiologic studies suggest that coffee use might protect against colorectal cancer. Inconsistencies as to the effect of coffee use and colorectal cancer between epidemiologic studies might be related to the type of coffee brew., Objective: We studied the effect of unfiltered coffee consumption on putative biomarkers for colonic cancer risk., Design: A total of 64 healthy volunteers (31 men and 33 women), with a mean age of 43 +/- 11 years were randomly assigned to two groups in a crossover design, with two intervention periods of 2 weeks separated by a washout period of 8 weeks. Treatments were 1 L of cafetière (French press) coffee daily or no coffee. At the end of each intervention period, fasting blood samples, colorectal biopsies and 48 h faeces were collected., Results: No effect of coffee on colorectal cell proliferation, assayed by estimating the Proliferating Cell Nuclear Antigen labelling index, was seen. Additionally, no effects were seen on the concentrations of faecal soluble bile acids and colorectal mucosal glutathione S-transferase activity. However, unfiltered coffee significantly increased the glutathione content in the colorectal mucosa by 8% and in plasma by 15%. Other aminothiols in plasma also increased on coffee., Conclusion: Unfiltered coffee does not influence the colorectal mucosal proliferation rate, but might increase the detoxification capacity and anti-mutagenic properties in the colorectal mucosa through an increase in glutathione concentration. Whether this effect indeed contributes to a lower colon cancer risk remains to be established.

Coffee beans contain the diterpene cafestol, which raises plasma cholesterol concentrations in humans. Daily consumption of 2 g coffee oil, which provides approximately 60 mg cafestol (equivalent to 5.7 mg cafestol/MJ), increases plasma cholesterol concentrations by 28%. We studied the effect of cafestol in coffee oil on gerbils and rats to determine whether the pathways that lead to cafestol-induced hypercholesterolemia in humans are also present in other species. We fed coffee oil from the same batch used in humans to female gerbils and rats. Gerbils were fed a semipurified diet containing 0.5% or 5% (w/w) coffee oil (equivalent to 8.7 and 86.8 mg cafestol/MJ, respectively) in the presence or absence of 0.05% (w/w) cholesterol for a period of 10 weeks. When compared with the gerbils fed no coffee oil, the addition of 0.5% coffee oil to the diets did not affect plasma cholesterol. Plasma cholesterol was significantly higher only when 5% coffee oil was fed, both in the absence (1.01 mmol/L, 33% higher) and presence (1.87 mmol/L, 70% higher) of dietary cholesterol. Liver weight was also significantly higher when 5% coffee oil was fed. Rats were also fed diets containing 0.5% or 5% coffee oil (equivalent to 8.7 and 86.8 mg cafestol/MJ) with and without 0.05% cholesterol for 8 weeks. Feeding 0.5% coffee oil compared with no coffee oil resulted in significantly higher plasma cholesterol levels throughout the study both in the absence (0.46 mmol/L, 27% higher) and presence (0.28 mmol/L, 15% higher) of dietary cholesterol. Diets containing 5% coffee oil appeared to be toxic. Thus, coffee oil diterpenes can result in higher plasma cholesterol in gerbils and rats. The failure to observe these effects in previous studies may be due to doses that were too low.

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.

The flavonoid quercetin is an antioxidant which occurs in foods mainly as glycosides. The sugar moiety in quercetin glycosides affects their bioavailability in humans. Quercetin-3-rutinoside is an important form of quercetin in foods, but its bioavailability in humans is only 20% of that of quercetin-4'-glucoside. Quercetin-3-rutinoside can be transformed into quercetin-3-glucoside by splitting off a rhamnose molecule. We studied whether this 3-glucoside has the same high bioavailability as the quercetin-4'-glucoside. To that end we fed five healthy men and four healthy women (19-57 y) a single dose of 325 micromol of pure quercetin-3-glucoside and a single dose of 331 micromol of pure quercetin-4'-glucoside and followed the plasma quercetin concentrations. The bioavailability was the same for both quercetin glucosides. The mean peak plasma concentration of quercetin was 5.0+/-1.0 micromol/L (+/-SE) after subjects had ingested quercetin-3-glucoside and 4.5+/-0.7 micromol/L after quercetin-4'-glucoside consumption. Peak concentration was reached 37 +/-12 min after ingestion of quercetin-3-glucoside and 27+/-5 min after quercetin-4'-glucoside. Half-life of elimination of quercetin from blood was 18.5+/-0.8 h after ingestion of quercetin-3-glucoside and 17.7+/-0.9 h after quercetin-4'-glucoside. We conclude that quercetin glucosides are rapidly absorbed in humans, irrespective of the position of the glucose moiety. Conversion of quercetin glycosides into glucosides is a promising strategy to enhance bioavailability of quercetin from foods.

Flavonoids are antioxidants present in plant foods. They occur mainly as glycosides, i.e. linked with various sugars. It is uncertain to what extent dietary flavonoid glycosides are absorbed from the gut. We investigated how the nature of the sugar group affected absorption of one major flavonoid, quercetin. Quercetin linked with glucose, i.e. quercetin glucoside and quercetin linked with rutinose, i.e. quercetin rutinoside, both occur widely in foods. When we fed these compounds to nine volunteers, the peak concentration of quercetin (Cmax) in plasma was 20 times higher and was reached (Tmax) more than ten times faster after intake of the glucoside (Cmax = 3.5+/-0.6 microM (mean +/- SE); Tmax < 0.5 h) than after the rutinoside (Cmax = 0.18+/-0.04 microM; Tmax = 6.0+/-1.2 h). The bioavailability of the rutinoside was only 20% of that of the glucoside. We suggest that quercetin glucoside is actively absorbed from the small intestine, whereas quercetin rutinoside is absorbed from the colon after deglycosylation. Absorption of other food components might also be enhanced by attachment of a glucose group.

Flavonoids are polyphenolic compounds that are ubiquitously present in foods of plant origin. Flavonoids are categorised into flavonols, flavones, catechins, flavanones, anthocyanidins, and isoflavonoids. They may have beneficial health effects because of their antioxidant properties and their inhibitory role in various stages of tumour development in animal studies. It is estimated that the human intake of all flavonoids is a few hundreds of milligram per day. Flavonoids present in foods used to be considered non-absorbable because they are bound to sugars as beta-glycosides. However, we found that human absorption of the quercetin glycosides from onions (52%) is far better than that of the pure aglycone (24%). The sugar moiety is an important determinant of their absorption and bioavailability. Flavonol glycosides might contribute to the antioxidant defences of blood. The average intake of the flavonols quercetin, myricetin and kaempferol and the flavones luteolin and apigenin in the Netherlands was 23 mg/day. The intake of these flavonols and flavones was inversely associated with subsequent coronary heart disease in some but not all prospective epidemiological studies. A protective effect of flavonols on cancer was found in one prospective study; two others showed no association. Thus the epidemiological evidence does not yet allow a decision on the involvement of flavonols in the etiology of either cardiovascular diseases or cancer.

Background: Hypercholesterolaemia is initially treated by diet. However, most studies of diet and cholesterol response have been carried out in men, and it is not known whether women react to diet to the same extent as men do. We therefore studied sex differences in the response of serum cholesterol and lipoproteins to diet., Materials and Methods: We measured the responses of serum cholesterol to a decrease in dietary saturated fat in seven trials involving 126 men and 147 women, to a decrease in dietary trans fat in two trials (48 men and 57 women) and to a decrease in dietary cholesterol in eight trials (74 men and 70 women). We also measured responses to the coffee diterpene cafestol, which occurs in unfiltered coffee, in nine trials (72 men and 61 women). All subjects were lean and healthy., Results: The response of total cholesterol (+/- standard deviation) to a decrease in the intake of saturated fat was greater in men (-0.62 +/- 0.39 mmol L-1) than in women (-0.48 +/- 0.39 mmol L-1; 95% confidence interval, 0.04-0.23 mmol L-1). The response of total cholesterol to a decrease in the intake of cafestol was also larger in men (-1.01 +/- 0.49 mmol L-1) than in women (-0.80 +/- 0.49 mmol L-1; 95% confidence interval, 0. 04-0.39 mmol L-1). Responses to trans fat and to dietary cholesterol did not differ between men and women., Conclusion: Men have larger responses of total and low-density lipoprotein cholesterol to saturated fat and cafestol than women do.

Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin. Over 4000 different flavonoids have been described. They may have beneficial health effects because of their antioxidant properties and their inhibitory role in various stages of tumour development in animal studies. An estimation of the total flavonoid intake is difficult, because only limited data on food contents are available. It is estimated that humans ingest a few hundreds of milligram per day. The average intake of the subclasses of flavonols and flavones in The Netherlands was 23 mg/day. The intake of flavonols and flavones was inversely associated with subsequent coronary heart disease in most but not all prospective epidemiological studies. A protective effect of flavonols on cancer was found in only one prospective study. Flavonoids present in foods were considered non-absorbable because they are bound to sugars as beta-glycosides. However, we found that human absorption of the quercetin glycosides from onions (52%) is far better than that of the pure aglycone (24%). Flavonol glycosides might contribute to the antioxidant defences of blood. Dietary flavonols and flavones probably do not explain the cancer-protective effect of vegetables and fruits; a protective effect against cardiovascular disease is not conclusive.

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.

The cholesterol concentration in the plasma is poorly regulated by the human organism and is therefore easily influenced by lifestyle. Indeed cholesterol levels differ between populations. An important question is how much diet can be held responsible for differences in cholesterol level between e.g. Finland and Japan at the beginning of the Seven Countries Study around 1960. This difference can partly be explained by a difference in saturated fat intake but there was probably an accumulation of both genetic cholesterol elevating factors present in the Finnish society and of cholesterol-lowering factors in the Japanese society. However, controlled trials do show a major effect of diet on cholesterol. With iso-caloric diets low in saturated fat and high in fibre a reduction in total cholesterol of 20-30% can be realized. The reduction can be larger if weight loss also occurs. Further reductions may occur when novel foods are introduced on the market e.g. margarines enriched with plant sterols that give an additional reduction in total cholesterol of about 10%. It can be concluded that diet can reduce total cholesterol levels substantially. The value of novel foods in this context has to be evaluated.

Tea is an important dietary source of flavonols in countries such as the Netherlands, the United Kingdom and Japan. Flavonols may have beneficial health effects because of their antioxidant properties and their inhibitory role in various stages of tumor development in animal studies. The association between flavonol intake and cancer risk was investigated in three prospective studies (Zutphen Elderly Study in the Netherlands, a Finnish cohort, and the Netherlands Cohort Study). Only one study (Finnish cohort) showed an inverse association with cancer mortality. The intake of flavonols with subsequent cardiovascular disease was studied in six prospective epidemiological studies. In some populations (Seven Countries Study, Zutphen Elderly Study, a Finnish cohort) a clear protective effect was observed. In a large US cohort, a protective effect was only found in a subgroup with previous history of coronary heart disease, whereas in Welsh men, flavonol intake, mainly from tea, was associated with an increased risk of coronary heart disease. These conflicting results may be due to confounding by coronary risk factors associated with tea consumption. The question of whether flavonols protect against cardiovascular disease remains still open; a protective effect of flavonols against cancer is less likely.

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.

Background: We determined the effect of oral ingestion of sucrose polyester, which was approved as a fat replacer in the United States, on gallbladder motility and on the release of cholecystokinin, the hormone that mediates gallbladder emptying., Objective: Our objective was to measure effects of sucrose polyester on gallbladder emptying and cholecystokinin release., Design: Eight healthy volunteers (3 men and 5 women) drank 60 mL sucrose polyester, digestible fat, or saline solution in a balanced crossover design on 3 separate days., Results: Mean (+/-SEM) gallbladder emptying, when integrated over time, was low in response to both sucrose polyester (-150 +/- 214 mL x 120 min) and saline solution (-89 +/- 123 mL x 120 min). In contrast, there was marked emptying in response to digestible fat (1069 +/- 253 mL x 120 min). Sucrose polyester did not affect plasma cholecystokinin concentrations (-9.3 +/- 15.0 pmol x 120 min/L), whereas digestible fat resulted in a significant increase (89.5 +/- 44.8 pmol x 120 min/L, P = 0.014) compared with saline solution (-3.0 +/- 13.8 pmol x 120 min/L)., Conclusions: Ingestion of sucrose polyester, in contrast with digestible fat, did not stimulate gallbladder emptying or release of cholecystokinin.

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.

Unsaturated fatty acids with their double bond in trans configuration raise serum low-density lipoprotein (LDL) cholesterol and lipoprotein(a) levels, and lower high-density lipoprotein (HDL) cholesterol in humans when substituted for cis unsaturated fatty acids in the diet. These effects should increase the risk of coronary heart disease, which is confirmed by epidemiological studies. Trans fatty acids are formed from cis unsaturated fatty acids during hydrogenation of vegetable oils in food industries. Until recently, major dietary sources of trans fatty acids in the Netherlands were frying fats, shortenings, and margarines, which in the past contained up to 50% of trans fatty acids. Nowadays, most shortenings and margarines sold in the Netherlands have a low trans fatty acid content due to manufacturing changes in the recent past. However, frying fats used in fast-food outlets still contain over 30% of trans fatty acids. French fries sold in these outlets provide 7-8 g of trans fatty acids per portion. Producers of frying fats for fast-food outlets therefore should also reduce the trans fatty acid content of their products as much as possible.

Replacement of saturated fat by the major dietary polyunsaturated fat linoleic acid reduces blood cholesterol concentrations and the risk of coronary artery disease. However, there is concern that long-term consumption of large amounts of linoleic acid might increase cancer risk. We reviewed the epidemiologic and experimental literature on linoleic acid intake and cancer risk and performed additional meta-analyses of risk estimates from case-control and prospective cohort studies. None of the combined estimates from within-population studies indicated a significantly increased risk of cancer with high compared with low intakes of linoleic acid or polyunsaturated fat. For case-control studies, the combined relative risks were 0.84 (95% CI: 0.71, 1.00) for breast, 0.92 (95% CI: 0.85, 1.08) for colorectal, and 1.27 (95% CI: 0.97, 1.66) for prostate cancer. For prospective cohort studies, combined relative risks were 1.05 (95% CI: 0.83, 1.34) for breast, 0.92 (95% CI: 0.70, 1.22) for colon, and 0.83 (95% CI: 0.56, 1.24) for prostate cancer. Ecologic comparisons of populations showed positive associations between cancer rates and per capita use of animal or saturated fat, but less so with per capita use of vegetable oil or polyunsaturated fat. Controlled studies of coronary artery disease in men did not, except for 1 study, show an increased cancer incidence after consumption of diets with a very high linoleic acid content for several years. Animal experiments indicated that a minimum amount of linoleic acid is required to promote growth of artificially induced tumors in rodents; but above this threshold, linoleic acid did not appear to have a specific tumor-promoting effect. Although current evidence cannot exclude a small increase in risk, it seems unlikely that a high intake of linoleic acid substantially raises the risks of breast, colorectal, or prostate cancer in humans.

Current dietary advice with a view to avoiding cardiovascular pathology is to replace fatty foodstuffs and those rich in saturated fat and cholesterol by food rich in complex carbohydrates. Although substitution of carbohydrates for fat lowers the blood level of low-density lipoprotein (LDL) cholesterol, it also lowers the level of high-density lipoprotein (HDL) cholesterol, thereby adversely influencing the risk profile for cardiovascular disease. Neither does a low fat diet appear to reduce obesity, another risk factor. A modern advice based on published research reads: obese persons should reduce their intake of saturated and trans-fatty acids by lowering the consumption of dairy fat, meat and hardened oils (bakery products and catering products fried in hardened fats), and in addition should consume less products with added sugars and refined starch. Carbohydrates should be provided by fruits, vegetables, leguminous plants and whole-wheat products. Persons of about the ideal weight should replace saturated and trans-fatty acids in their diet by unsaturated plant oils, and products with refined carbohydrates by fruits, vegetables and whole-wheat products.

Methods: In the present study, we have investigated the effects of intraduodenal perfusion of long-chain and medium-chain triglycerides and of sucrose polyester on the release of peptide YY in healthy men., Results: Perfusion of medium-chain triglycerides (180 mmol fatty acids) increased the plasma concentration of peptide YY from 7.9 pmol L(-1) (SEM 0.2, n=8) to 10.7 pmol L(-1) (SEM 0.5, n=8), whereas perfusion of long-chain triglycerides (180 mmol fatty acids) had a significantly greater effect, increasing peptide YY concentration from 8 6 pmol L(-1) (SEM 0.2, n=8) to 18.9 pmol L(-1) (SEM 2.4, n=8, P < 0.008). A smaller quantity of long-chain triglycerides (90 mmol fatty acids) increased plasma concentration of peptide YY from 7.4 pmol L(-1) (SEM 0.4, n=8) to 13.3 pmol L(-1) (SEM 1.5, n=8), whereas sucrose polyester (90 mmol fatty acids) did not change peptide YY concentration. In a previous study, we investigated gastrin-stimulated gastric acid output in response to these treatments. The correlation between increases in peptide YY in response to all treatments and the decrease in acid output was r=0.72 (n=48, P < 0.0001). These results show that both long-chain and medium-chain triglycerides, but not sucrose polyester, stimulate the release of peptide YY., Conclusion: We speculate that peptide YY may play an important role in the inhibition of gastrin-stimulated gastric acid secretion by long-chain and medium-chain triglycerides.

Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin. Over 4000 different flavonoids have been described, and they are categorized into flavonols, flavones, catechins, flavanones, anthocyanidins, and isoflavonoids. Flavonoids have a variety of biological effects in numerous mammalian cell systems, as well as in vivo. Recently much attention has been paid to their antioxidant properties and to their inhibitory role in various stages of tumour development in animal studies. Quercetin, the major representative of the flavonol subclass, is a strong antioxidant, and prevents oxidation of low density lipoproteins in vitro. Oxidized low density lipoproteins are atherogenic, and are considered to be a crucial intermediate in the formation of atherosclerotic plaques. This agrees with observations in epidemiological studies that the intake of flavonols and flavones was inversely associated with subsequent coronary heart disease. However, no effects of flavonols on cancer were found in these studies. The extent of absorption of flavonoids is an important unsolved problem in judging their many alleged health effects. Flavonoids present in foods were considered non-absorbable because they are bound to sugars as beta-glycosides. Only free flavonoids without a sugar molecule, the so-called aglycones were thought to be able to pass through the gut wall. Hydrolysis only occurs in the colon by microorganisms, which at the same time degrade flavonoids. We performed a study to quantify absorption of various dietary forms of quercetin. To our surprise, the quercetin glycosides from onions were absorbed far better than the pure aglycone. Subsequent pharmacokinetic studies with dietary quercetin glycosides showed marked differences in absorption rate and bioavailability. Absorbed quercetin was eliminated only slowly from the blood. The metabolism of flavonoids has been studied frequently in various animals, but very few data in humans are available. Two major sites of flavonoid metabolism are the liver and the colonic flora. There is evidence for O-methylation, sulfation and glucuronidation of hydroxyl groups in the liver. Bacterial ring fission of flavonoids occurs in the colon. The subsequent degradation products, phenolic acids, can be absorbed and are found in urine of animals. Quantitative data on metabolism are scarce.

Dietary supplementation with n-3 fatty acids from fish oil alleviates inflammation in various chronic inflammatory disease states. Reductions in the production of pro-inflammatory cytokines interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) have been seen in humans after short-term n-3 fatty acid supplementation. We investigated long-term effects of dietary n-3 fatty acids on circulating cytokine concentrations and on ex vivo stimulated whole-blood production of IL-1 beta, TNF-alpha and interleukin 1 receptor antagonist (IL-1Ra), the naturally occurring antagonist of IL-1. A total of 58 monks with a mean age of 56 years were randomized into four groups and their diets were supplemented with 0, 3, 6, or 9 g of fish oil, providing 0, 1.06, 2.13 or 3.19 g of n-3 fatty acids per day. Subjects received equal amounts of saturated fatty acids, vitamin E and cholesterol. Compliance was excellent and erythrocyte fatty acid profiles closely reflected the amounts of n-3 fatty acids ingested. In the group receiving 9 g of fish oil per day, no influence of n-3 fatty acids on circulating cytokine concentrations was observed relative to placebo. Endotoxin-stimulated whole-blood cytokine production was measured at 26 and 52 weeks after the start and at 4, 8 and 26 weeks after cessation of supplementation. In all groups, the production of IL-1 beta and IL-1Ra was higher during supplementation than afterwards. However, no differences in cytokine production were noted between the placebo group and the various treatment groups at any point in time. Our results suggest that long-term supplementation of fish oil does not affect ex vivo cytokine production in man.

Quercetin is a strong antioxidant and a major dietary flavonoid. Epidemiological studies suggest that consumption of quercetin protects against cardiovascular disease, but its absorption in man is controversial. We fed nine subjects a single large dose of onions, which contain glucose conjugates of quercetin, apples, which contain both glucose and non-glucose quercetin glycosides, or pure quercetin-3-rutinoside, the major quercetin glycoside in tea. Plasma levels were then measured over 36 h. Bioavailability of quercetin from apples and of pure quercetin rutinoside was both 30% relative to onions. Peak levels were achieved less than 0.7 h after ingestion of onions, 2.5 h after apples and 9 h after the rutinoside. Half-lives of elimination were 28 h for onions and 23 h for apples. We conclude that conjugation with glucose enhances absorption from the small gut. Because of the long half-lives of elimination, repeated consumption of quercetin-containing foods will cause accumulation of quercetin in blood.

Tissue levels of n-3 fatty acids reflect dietary intake, but quantitative data about rate of incorporation and levels as a function of intake are scarce. We fed 58 men 0, 3, 6, or 9 g/d of fish oil for 12 months and monitored fatty acids in serum cholesteryl esters, erythrocytes, and subcutaneous fat during and after supplementation. Eicosapentaenoic acid (EPA) in cholesteryl esters plateaued after 4-8 weeks; the incorporation half-life was 4.8 days. Steady-state levels increased by 3.9 +/- 0.3 mass % points (+/- SE) for each extra gram of EPA eaten per day. Incorporation of docosahexaenoic acid (DHA) was erratic; plateau values were 1.1 +/- 0.1 mass % higher for every g/d ingested. Incorporation of EPA into erythrocyte membranes showed a half-life of 28 days; a steady state was reached after 180 days. Each g/d increased levels by 2.1 +/- 0.1 mass %. C22:5n-3 levels increased markedly. Changes in DHA were erratic and smaller. EPA levels in adipose tissue rose also; the change after 6 months was 67% of that after 12 months in gluteal and 75% in abdominal fat. After 12 months each gram per day caused an 0.11 +/- 0.01 mass % rise in gluteal fat for EPA, 0.53 +/- 0.07 for C22:5n-3, and 0.14 +/- 0.03 for DHA. Thus, different (n-3) fatty acids were incorporated with different efficiencies, possibly because of interconversions or different affinities of the enzymatic pathways involved. EPA levels in cholesteryl esters reflect intake over the past week or two, erythrocytes over the past month or two, and adipose tissue over a period of years. These findings may help in assessing the intake of (n-3) fatty acids in epidemiological studies.

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.

Objective: Unfiltered coffee raises serum LDL cholesterol in humans, owing to the presence of the diterpenes cafestol and kahweol. Norwegians with a chronic high intake of unfiltered coffee also has elevated serum levels of lipoprotein(a), an LDL-like particle which is insensitive toward dietary interventions. We now experimentally studied the influence of coffee diterpenes on lipoprotein(a) levels., Design: Four randomised controlled trials., Subjects: Healthy, normolipidemic volunteers., Interventions: Coffee, coffee oil, and pure diterpenes for 4-24 weeks., Main Outcome Measures: The circulating level of lipoprotein(a)., Results: In 22 subjects drinking five to six strong cups of cafetiere coffee per day, the median fall in lipoprotein(a) was 1.5 mg/dL after two months (P = 0.03), and 0.5 mg/dL after half a year (P > 0.05), relative to 24 filter coffee drinkers. Coffee oil doses equivalent to 10-20 cups of unfiltered coffee reduced lipoprotein(a) levels by up to 5.5 mg/dL (P < 0.05) in two separate trials (n = 12-16 per group). A purified mixture of cafestol and kahweol, as well as cafestol alone, were also effective in reducing Lp(a) levels (n = 10). Averaged over the four trials, each 10 mg/d of cafestol (plus kahweol)--the amount present in two to three cups of cafetiere coffee--decreased Lp(a) levels by 0.5 mg/dL or 4% from baseline values after four weeks (n = 63)., Conclusions: Coffee diterpenes are among the few dietary exceptions shown to influence serum lipoprotein(a) levels. However, the Lp(a)-reducing potency of coffee diterpenes may subside in the long run, and their adverse side effects preclude their use as lipoprotein(a)-reducing agents.

The fatty acid composition of serum cholesteryl esters is used as a qualitative biomarker of fatty acid intake, but quantitative data are scarce. Between 1987 and 1992, the authors fed various fatty acids in four controlled trials to 232 healthy Dutch volunteers and measured the proportion of fatty acids in participants' cholesteryl esters. Each 10% of energy fed as linoleic acid (18:2) raised the proportion of linoleic acid in cholesteryl esters by 9.3 g per 100 g of fatty acids (standard deviation (SD) 3.1). For oleic acid (cis-18:1), this figure was 6.5 g/100 g (SD 1.7); for trans fatty acids (trans-18:1), it was 1.1 (SD 0.5); for stearic acid (18:0), 1.0 (SD 0.4); for palmitic acid (16:0), 1.7 (SD 0.5); for myristic acid (14:0), 2.1 (SD 0.7); and for a mixture of saturated fatty acids (12:0, 14:0, and 16:0), it was 2.2 g/100 g (SD 1.0). The coefficient of variation of the responses was fairly constant, indicating that changes in intake for each of these fatty acids can be monitored with similar precision. These data can be used to estimate the degree of compliance in experimental studies involving exchanges of single dietary fatty acids. Most fatty acids in cholesteryl esters may also be used in observational studies to estimate differences in intake. However, because of multiple simultaneous differences in fatty acid intake between free-living individuals and between populations, such data cannot provide information on absolute intake of fatty acids.

Protein-energy malnutrition is thought to be widespread in hospitalized patients. However, the specificity of indexes used to assess malnutrition is uncertain. We therefore assessed the rate of false-positive diagnoses of malnutrition when biochemical-anthropometric indexes were applied to healthy subjects. Nutritional status was assessed in 175 healthy blood donors (aged 44.2 +/- 13.4 y) and in 34 highly fit elderly volunteers (aged 74.7 +/- 3.6 y) participating in the Nijmegen Four Days Walking March. We investigated both the Nutritional Risk Index [(1.489 x albumin) + (41.7 x present/usual weight)] and the Maastricht Index [20.68-(0.24 x albumin, g/L)-(19.21 x serum transthyretin, g/L)-(1.86 x lymphocytes, 10(6)/L)-(0.04 x ideal weight)]. We found previously that 52-64% of nonsurgical hospitalized patients were malnourished according to these indexes. In the present study, 1.9% of the 209 volunteers had apparent malnutrition according to the Nutritional Risk Index and 3.8% according to the Maastricht Index. The prevalence of apparent malnutrition in the elderly volunteers was 5.9% and 20.6%, respectively. The rate of false-positive diagnoses was acceptably low in those aged < 70 y with both the Nutritional Risk Index and the Maastricht Index; therefore, the use of these indexes will not cause a clinically significant increase in the prevalence of malnutrition because patients who are not malnourished are included. The high percentage of spurious malnutrition in the elderly limits the use of the Maastricht Index to subjects aged < 70 y.

Intake of trans fatty acids unfavorably affects blood lipoproteins. As margarines are a major source of trans, claims for the advantages of margarines over butter need to be scrutinized. Here we review dietary trials that directly compared the effects of butter and margarine on blood lipids. We identified 20 studies in which subjects had stable body weights, and margarine and butter were exchanged in the diet at constant energy and fat intake. We calculated the changes in average blood lipid levels between study diets (49 comparisons) as a function of the percentage of calories as margarine substituted for butter. Replacing 10% of calories from butter by hard high-trans stick margarines lowered total serum cholesterol by 0.19, LDL by 0.11, and HDL by 0.02 mmol/l, and did not affect the total/HDL cholesterol ratio. Soft low-trans tub margarines decreased total cholesterol by 0.25 and LDL by 0.20 mmol/l, did not affect HDL, and decreased the total/HDL cholesterol ratio by 0.20. Based on the total/HDL cholesterol ratio, replacement of 30 g of butter per day by soft tub margarines would theoretically predict a reduction in coronary heart disease risk of 10%, while replacement of butter by hard, high-trans margarines would have no effect. Replacing butter by low-trans soft margarines favorably affects the blood lipoprotein profile and may reduce the predicted risk of coronary heart disease, but high-trans hard margarines probably confer no benefit over butter.

Quercetin and related flavonoids are anticarcinogenic in rats, but little is known about human intakes. The intake of five major flavonols and flavones was calculated using 1-day dietary records of 17 volunteers from 14 countries, and using both 3-day records and a food frequency questionnaire of eight Dutch adults. Total consumption (+/- SD) was 27.6 +/- 19.5 mg/day in the international subjects, 34.1 +/- 31.2 mg/day in the Dutch adults according to 3-day records, and 41.9 +/- 23.7 mg/day according to questionnaires. Quercetin contributed 68-73%, and kaempferol 22-29%, the major sources being tea and onions. A brief food frequency questionnaire may be a suitable method for ranking individuals by flavonol intake.

Quercetin, a dietary antioxidant flavonoid, has anticarcinogenic properties. We quantified the absorption of quercetin in ileostomists. Absorption was 52 +/- 5% for quercetin glucosides from onions, 17 +/- 15% for quercetin rutinoside, and 24 +/- 9% for quercetin aglycone. The plasma quercetin concentration in subjects with an intact colon, after ingestion of fried onions, apples and pure quercetin rutinoside, decreased slowly with elimination half-lives of about 25 h. Thus, repeated dietary intake of quercetin will lead to accumulation in plasma. The relative bioavailability of quercetin from apples and rutinoside was one-third of that from onions. Absorption kinetics and bioavailibility might be determined by the type of glycoside. Dietary quercetin could increase the antioxidant capacity of blood plasma.

Acetylsalicylic acid is effective in the prevention of cardiovascular disease. It was suggested that fruits and vegetables provide unknown amounts of acetylsalicylic acid. We could not find any acetylsalicylic acid in 30 foods using HPLC with fluorescence detection (detection limits: 0.02 mg/kg for fresh, and 0.2 mg/kg for dried products). We showed that urinary excretion of salicylates is a valid indicator for intake, and found a median salicylate excretion of 10 micromol (1.4 mg) in 24 h urine of 17 volunteers eating a variety of diets. Our data suggest that the content of (acetyl)salicylic acid of diets may be too low to affect disease risk.

Most dietary fatty acids contain at least one double bond, which is usually in the cis configuration. However, biohydrogenation in the rumen of cows and sheep, or catalytic hydrogenation of vegetable oils in the food industries, will convert some of the cis double bonds to the trans configuration. Trans fatty acid intake in western Europe and North America probably ranges from 5 to 15 g/day. Major dietary sources are frying fats used in industrial food preparation, margarines, and other spreads. In the past, margarines contained up to 50% trans fatty acids; however, these are now being phased out. Trans fatty acids raise serum low density lipoprotein (LDL) cholesterol and lower high density lipoprotein (HDL) cholesterol in humans when substituted for cis unsaturated fatty acids in the diet. These effects may be mediated by the cholesteryl ester transfer protein. Trans fatty acids also increase lipoprotein (a) levels relative to other fatty acids. The effects of trans fatty acids on the risk profile for coronary heart disease are thus unfavorable, and labels of food products should state the trans fatty acid content.

Replacement of dietary fat by sucrose polyester reduces fat intake. However, little is known about the effects of sucrose polyester on gastrointestinal function. To investigate the effect on gastric acid secretion and on release of cholecystokinin into plasma, we perfused eight healthy male volunteers intraduodenally with sucrose polyester, digestible fat, or saline on separate days in random order. Intraduodenal perfusion of sucrose polyester did not suppress gastrin-stimulated gastric acid secretion (-1.8 +/- 6.8%) whereas digestible fat suppressed gastric acid secretion by 64 +/- 9% (P = 0.001) compared with saline. Sucrose polyester did not affect plasma cholecystokinin concentrations (-12.8 +/- 9.3 pmol.30 min/L) whereas perfusion with digestible fat resulted in a significant increase (31.7 +/- 9.3 pmol.30 min/L, P = 0.017) compared with saline. We conclude that sucrose polyester, in contrast with digestible fat, does not inhibit gastrin-stimulated gastric acid secretion or stimulate release of cholecystokinin.