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The nutritional state, and/or the ingestion of specific nutrients, is/are able to modify drug disposition, by interfering with drug absorption, distribution, storage, and metabolism. Recent data report that nutrients interfere with drug metabolism either by modifying key enzymes of phase I (cytochromeP450 dependent mixed function oxidase) and II (glucuronosyl, sulfonyl- ... transferases), or by modulating coenzymes availability (NADPH, UDPglucuronic acid...). Food components involved in drug metabolism modifications are either macro-nutrients (carbohydrates, lipids, proteins, ethanol), micronutriments (vitamins, minerals), or phytochemicals. Drug-nutrients interactions may be beneficials, and thus could constitute, i.e. a way to improve drug therapeutic index, or generate adverse effects.

Several nondigestible but fermentable dietary carbohydrates are able to regulate lipemia and triglyceridemia in both humans and animals. The mechanism of their serum lipid-lowering effect remains to be elucidated. Oligofructose, which is a mixture of nondigestible and fermentable fructans, can decrease triacylglycerol in VLDL when given to rats. The triacylglycerol-lowering action of oligofructose is due to a reduction of de novo fatty acid synthesis in the liver through inhibition of all lipogenic enzymes, namely acetyl-CoA carboxylase (EC 6.4.1.2), fatty acid synthase, malic enzyme (EC 1.1.1.40), ATP citrate lyase (EC 4.1.3.8), and glucose-6-phosphate dehydrogenase (EC 1.1.1.49). Our results suggest that oligofructose decreases lipogenic enzyme gene expression. Postprandial insulin and glucose concentrations are low in the serum of oligofructose-fed animals and this could explain, at least partially, the metabolic effect of oligofructose. Moreover, some events occurring in the gastrointestinal tract after oligofructose feeding could be involved in the antilipogenic effect of this fructan: the production of propionate through fermentation, a modulation of the intestinal production of incretins (namely glucose-dependent insulinotropic peptide and glucagon-like peptide-1), or the modification of the availability of digestible carbohydrates. Recent studies showed that the hypotriglyceridemic effect of fructans also occurs in humans.

In rats, a high carbohydrate fat-free (HCFF) diet, given after fasting, induces both hepatic lipogenic and glycogenic enzymes. In the present study, we evaluated the involvement of Kupffer cells in the metabolic events occurring in the liver during the fasting-refeeding transition. Male Wistar rats were fasted for 48 h and received an intravenous injection of either NaCl 0.9% (Gd-) or 10 mg/kg GdCl(3) (Gd+), an inhibitor of Kupffer cells, then fed for 12 h with a HCFF diet. The comparison of colloidal carbon uptake was similar in rats fasted and in rats fasted and then refed a HCFF diet, thus indicating that refeeding does not affect per se Kupffer cell phagocytic activity. The inhibition of Kupffer cells by GdCl(3) did not affect fatty acid synthase (FAS) induction, as shown by the analysis of both FAS mRNA and activity; refeeding a HCFF diet increased the hepatic triglyceride and glycogen content to the same extent in Gd+ and Gd- rats. Our results do not support the involvement of Kupffer cells in the metabolic events occurring in the liver tissue by feeding a HCFF diet after fasting. However, the discussion supports the involvement of Kupffer cells in the modulation of the hepatic lipid metabolism by other nutrients than carbohydrates.

The presence of CB(2) receptors was reported in the rat basophilic cell line RBL-2H3 and N-palmitoylethanolamide was proposed as an endogenous, potent agonist of this receptor. We synthesized a series of 10 N-palmitoylethanolamide homologues and analogues, varying by the elongation of the fatty acid chain from caproyl to stearoyl and by the nature of the amide substituent, respectively, and evaluated the affinity of these compounds to cannabinoid receptors in the rat spleen, RBL-2H3 cells and CHO-CB(1) and CHO-CB(2) receptor-transfected cells. In rat spleen slices, CB(2) receptors were the predominant form of the cannabinoid receptors. No binding of [(3)H]SR141716A was observed. [(3)H]CP-55,940 binding was displaced by WIN 55,212-2 and anandamide. No displacement of [(3)H]CP-55,940 or [(3)H]WIN 55,212-2 by palmitoylethanolamide derivatives was observed in rat spleen slices. In RBL-2H3 cells, no binding of [(3)H]CP-55,940 or [(3)H]WIN 55,212-2 could be observed and conversely, no inhibitory activity of N-palmitoylethanolamide derivatives and analogues was measurable. These compounds do not recognize the human CB(1) and CB(2) receptors expressed in CHO cells. In conclusion, N-palmitoylethanolamide was, in our preparations, a weak ligand while its synthesized homologues or analogues were essentially inactive. Therefore, it seems unlikely that N-palmitoylethanolamide is an endogenous agonist of the CB(2) receptors but it may be a compound with potential therapeutic applications since it may act via other mechanisms than cannabinoid CB(1)-CB(2) receptor interactions.

The possible influence of dietary non-digestible carbohydrates (15% oligofructose, inulin or pectin incorporated in basal diet) on the growth of intramuscularily transplanted mouse tumors, from 2 tumor lines (TLT and EMT6), was investigated. The results were evaluated by regular tumor measurements with Vernier caliper. Mean tumor surface in experimental groups was compared with that in animals of control group fed basal diet containing starch as the only carbohydrate. The growth of both tumor lines was significantly inhibited by supplementation of non-digestible carbohydrates.

The present study was aimed at answering the question why feeding rats an oligofructose (OFS) supplemented diet could cause a significant reduction in plasma lipid levels. Daily administration of a 10% (w/w) OFS-containing diet to normolipidemic male rats resulted in a decrease in plasma triglycerides, phospholipids and cholesterol. The triglyceride-lowering effect was observed after one week and lasted for at least 16 wk and was associated with a reduction in plasma very low density lipoproteins, indicating that the hypolipidemic effect of OFS may be due to changes in liver lipid metabolism. We therefore tested whether OFS feeding modified the capacity of the liver to synthesize triglycerides from free fatty acids. Hepatocytes isolated from livers of control and OFS-fed rats were incubated in the presence of [1-14C]palmitate, and both intracellular and extracellular [14C]triglyceride formation were quantified. We found that chronic feeding of an OFS-supplemented diet to rats significantly reduced the capacity of isolated hepatocytes to synthesize triglycerides from palmitate. The results suggest that, like other soluble dietary fibers, OFS significantly alters liver lipid metabolism, resulting over time in a significant reduction in plasma triglyceride, phospholipid and cholesterol levels.

As previously demonstrated, chronic administration of phenobarbital (0.05% in the drinking water) and of nafenopin (0.1% in the diet) increases the incidence and the kinetics of appearance of liver cancers. If bile acids play a key role in liver carcinogenesis, it might thus be expected that treatments like phenobarbital or nafenopin, which positively modulate that process, also modify their hepatic pool. The aim of the present study was to analyze the modifications of the liver bile acid pool during the modulation of liver carcinogenesis by phenobarbital and nafenopin. The animals were submitted to the hepatocarcinogenic initiation-selection (IS) procedure adapted from Solt and Farber. As compared to basal diet, the chronic feeding of phenobarbital significantly increased the total concentrations of liver bile acids both at weeks 9 and 17. That increase was mainly due to a change in the concentration of beta-muricholic acid and hyodeoxycholic acid and, to a lesser extent, of chenodeoxycholic acid and alpha-muricholic acid. In contrast, feeding a diet containing nafenopin led to a significant decrease in the concentration of liver bile acids, due to a complete disappearance of chenodeoxycholic acid and muricholic acid, and a decrease in the concentration of hyodeoxycholic acid. Carcinomas appearing in IS phenobarbital-treated rats contain fewer bile acids than the surrounding parenchyma (because of the decrease in deoxycholic acid and ursodeoxycholic acid) whereas the malignant tumors appearing in IS nafenopin-treated rats have essentially the same pattern of bile acids as the surrounding parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS)

Oligofructose, a natural food ingredient, is the product of partial enzymatic hydrolysis of inulin. This nondigestible oligosaccharide is fermented by colonic bacteria to produce mainly short-chain fatty acids, L-lactate, and CO2 and the energy necessary for bacterial growth. It also increases fecal mass. Based on biochemical balance charts for carbon atoms, metabolic pathways, and energy yield to the host, the caloric value of a fructosyl unit of oligofructose is calculated to be 25-35% that of a digested molecule of hexose. The caloric value of oligofructose is thus likely to be close to 1 kcal/g.

Until now, the cytotoxicity of the bile acids was mostly seen as being inversely associated with their degree of lipophilicity. The present study aimed at comparing the hepatotoxicity of cholic acid (CA), deoxycholic acid (DCA) and lithocholic acid (LCA), which are respectively, tri-, di- and monohydroxylated bile acids. For in vivo studies, the bile acids have been given at the dose of 0.5% or 1% in the diet of male Wistar rats for 2 weeks. The histological analysis of the liver, and the measurement of serum parameters of cytotoxicity and cholestasis (aminotransferases activity, bilirubin and total bile acids concentration), indicate that, among the bile acids tested, DCA is the most hepatotoxic, at both doses, while CA is the least hepatotoxic and cholestatic compound. Moreover, DCA is the only bile acid which, when given at the dose of 0.5%, induces lipid peroxidation in the liver, as evidenced by the measurement of thiobarbituric reactive substances in liver homogenates. The analysis of bile acids in liver homogenates by gas liquid chromatography revealed that feeding the animals with DCA results in its hepatic accumulation. Feeding rats with LCA or CA only slightly modifies the proportion of tri-, di- and monohydroxylated bile acids in the liver, as compared to controls. An in vitro experiment aimed at studying the hepatocellular lysis induced in vitro by the three bile acids by measuring the release of lactate dehydrogenase in the incubation medium of surviving hepatocytes in suspension. At a concentration of 1 mM, only DCA induces a significant cellular lysis, while at this concentration the lytic effects of CA and LCA are progressive and time-dependent. From this study, we gather that the hepatotoxicity of bile acids does not necessarily depend on their degree of hydroxylation. Our results are in accordance with some studies in rat hepatocarcinogenesis, showing a predominant initiating and promoting effects of DCA, as compared to LCA.