Cafestol is a diterpene present in unfiltered coffees. It is the most potent cholesterol-elevating compound present in the human diet. However, the precise mechanisms underlying this effect are still unclear. In contrast, cafestol is also known as a hepatoprotective compound which is likely to be related to the induction of glutathione biosynthesis and conjugation. In the present study we investigated whole body distribution, biliary excretion and portal bioavailability of cafestol in mice. First, dissection was used to study distribution. Five hours after an oral dose with (3)H labeled cafestol, most activity was found in small intestine, liver and bile. These results were confirmed by quantitative whole body autoradiography in a time course study which also showed elimination of all radioactivity within 48 hours after administration. Next, radiolabeled cafestol was dosed i.v. to bile duct cannulated mice. Five hours post dose 20% of the radioactivity was found in bile. Bile contained several metabolites but no parent compound. After intestinal administration of radioactive cafestol to portal vein cannulated mice, cafestol was shown to be rapidly absorbed into the portal vein as parent compound, a glucuronide and an unidentified metabolite. From the presence of a glucuronide in bile that can be deconjugated by a bacterial enzyme and the prolonged absorption of parent compound from the GI tract we hypothesize that cafestol undergoes enterohepatic cycling. Together with our earlier observation that epoxidation of the furan ring occurs in liver these findings merit further research on the process of accumulation of this coffee ingredient in liver and intestinal tract.

Conjugated linoleic acid (CLA) is consumed widely as a supplement. It causes hepatomegaly in animals, but toxicological data in humans are limited. We therefore studied the effect of a high daily intake of CLA on liver and kidney function in healthy subjects. Twenty subjects received 14.6 g cis-9,trans-11 CLA and 4.7 g trans-10,cis-12 CLA isomers a day for 3 weeks. Liver and kidney function was measured at 0, 3, 7, 10, 16, and 21 days. Mean values of all tests remained within normal limits. Lactate dehydrogenase (mean +/- sd) increased from 290.9 +/- 43.6 U/L to 322.5 +/- 60.7 U/L (p=0.04) on day 21. One subject exceeded the upper limit of normal of 450 U/L on day 21, to 472 U/L and another showed an isolated elevation to 555 U/L on day 7. Gamma-glutamyltranspeptidase increased from 12.1 +/- 5.9 U/L to 13.5 +/- 6.2 U/L (p=0.002). No one exceeded the upper limit of 50 U/L for men and 40 U/L for women. A daily intake of 19.3 g CLA for 3 weeks does not produce clinically relevant effects on markers of liver and kidney function in healthy volunteers. Registered under ClinicalTrials.gov Identifier no. NCT00449462.

Observational studies have shown an association between low plasma cholesterol levels and increased risk of cancer, whereas most randomized clinical trials involving cholesterol-lowering medications have not shown this association. Between 1997 and 2002, the authors assessed the association between plasma cholesterol levels and cancer risk, free from confounding and reverse causality, in a Mendelian randomization study using apolipoprotein E (ApoE) genotype. ApoE genotype, plasma cholesterol levels, and cancer incidence and mortality were measured during a 3-year follow-up period among 2,913 participants in the Prospective Study of Pravastatin in the Elderly at Risk. Subjects within the lowest third of plasma cholesterol level at baseline had increased risks of cancer incidence (hazard ratio (HR)= 1.90, 95% confidence interval (CI): 1.34, 2.70) and cancer mortality (HR = 2.03, 95% CI: 1.23, 3.34) relative to subjects within the highest third of plasma cholesterol. However, carriers of the ApoE2 genotype (n = 332), who had 9% lower plasma cholesterol levels than carriers of the ApoE4 genotype (n = 635), did not have increased risk of cancer incidence (HR = 0.86, 95% CI: 0.50, 1.47) or cancer mortality (HR = 0.70, 95% CI: 0.30, 1.60) compared with ApoE4 carriers. These findings suggest that low cholesterol levels are not causally related to increased cancer risk.

Cafestol and kahweol are diterpene compounds present in unfiltered coffees. Cafestol is known as the most potent cholesterol-raising agent that may be present in the human diet. Remarkably, the mechanisms behind this effect have only been partly resolved so far. Even less is known about the metabolic fate of cafestol and kahweol. From the structure of cafestol, carrying a furan moiety, we hypothesized that epoxidation may not only be an important biotransformation route but that this also plays a role in its effects found. In bile duct-cannulated mice, dosed with cafestol, we were able to demonstrate the presence of epoxy-glutathione (GSH) conjugates, GSH conjugates and glucuronide conjugates. In addition, it was shown that cafestol was able to induce an electrophile-responsive element (EpRE). Using a murine hepatoma cell line with a luciferase reporter gene under control of an EpRE from the human NQO1 regulatory region, we also found that metabolic activation by CYP450 enzymes is needed for EpRE induction. Furthermore, raising intracellular GSH resulted in a decrease in EpRE-mediated gene induction, whereas lowering intracellular GSH levels increased EpRE-mediated gene induction. In conclusion, evidence suggests that cafestol induces EpRE, apparently via a bioactivation process that possibly involves epoxidation of the furan ring. The epoxides themselves appear subject to conjugation with GSH. The effects on EpRE can also explain the induction of GSH which seems to be involved in the reported beneficial effects of cafestol, for example, when administered with aflatoxin B1 or other toxic or carcinogenic compounds.

Aims To determine the effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) from fish on the incidence of recurrent ventricular arrhythmia in implantable cardioverter defibrillator (ICD) patients by combining results from published trials. Methods and results We searched in the Medline, EMBASE, and Cochrane databases and performed a meta-analysis on all three available trials on fish oil and ventricular arrhythmia. Furthermore, we pooled individual data of two of these randomized, double-blind, placebo-controlled trials (Raitt et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA 2005;293:2884-2891 and Brouwer et al. Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA 2006;295:2613-2619). The main outcome was time to first confirmed ventricular fibrillation (VF) or ventricular tachycardia (VT) combined with death for the meta-analysis, and time to first spontaneous confirmed VF or VT for the pooled analysis. The meta-analysis (n = 1148) showed no convincing protective effect of fish oil (RR 0.90; 95% CI 0.67-1.22). The hazard ratio for the subgroup of patients with coronary artery disease at baseline (0.79; 0.60-1.06) tended towards a protective effect. The pooled analysis (n = 722) showed that time to appropriate ICD intervention was similar for fish oil and placebo treatment (log-rank P = 0.79). Conclusion These findings do not support a protective effect of omega-3 PUFAs from fish oil on cardiac arrhythmia in all patients with an ICD. Current data neither prove nor disprove a beneficial or a detrimental effect for subgroups of patients with specific underlying pathologies.

Diets high in saturated fat, trans fat and glycaemic load and low in fibre and polyunsaturated fat are associated with a 25 to 50% increase in the risk of type 2 diabetes. However, obesity increases this risk by 500 to 1000%. Effects ascribed to dietary composition might therefore be due to unmeasured effects of body size. In clinical trials, a weight loss of 3-5 kg plus twice to min of walking per day reduced the incidence of diabetes by 58%. The size of this effect is remarkable. It points to the solution to the diabetes epidemic, which is to reconstruct cities so as to make people eat less and move more. There is an analogy here with the cholera epidemics, which also could be solved only by changing the urban environment.