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1 The transepithelial transport of the P-adrenoceptor blocking drug, celiprolol, was investigated in monolayers of the well differentiated human intestinal epithelial cell line, Caco-2.2 The basal-to-apical transport (secretion) of ['4C]-celiprolol (50 jLM) was 5 times higher than apical-tobasal transport (absorption). In the presence of an excess (5 mM) of unlabelled celiprolol the basal-toapical transport was reduced by more than 80%, whereas the apical-to-basal transport remained unchanged. 3 Net celiprolol secretion obtained in the concentration range 0.01 to 5 mM displayed saturable kinetics with an apparent Km of 1.00 ± 0.23 mm and Vm,, of 113 ± 11 pmol/106 cells min-'. These results are consistent with saturable active secretion and provide an explanation for the dose-dependent bioavailability of celiprolol. 4 The secretion of celiprolol was sensitive to pH, and decreased in the absence of sodium and in the presence of ouabain, suggesting that transport was coupled to proton and sodium gradients. 5 The secretion of celiprolol was inhibited by substrates for P-glycoprotein (vinblastine, verapamil and nifedipine) and either inhibited or stimulated by typical substrates for the renal organic cation-H+ exchanger (cimetidine, N'-methylnicotinamide, tetraethylammonium and choline), suggesting that there are at least two distinct transport systems.6 The secretion of celiprolol was also inhibited by other P-adrenoceptor blocking drugs (acebutolol, atenolol, metoprolol, pafenolol and propranolol) and by the diuretics, acetazolamide, chlorthalidone and hydrochlorothiazide, suggesting that the clinically observed effect of chlorthalidone on the bioavailability of celiprolol occurs at the level of the intestinal epithelium.

Dietary flavonoids represent a family of polyphenol compounds found in common food items derived from plants. Depending on structural features, flavonoids can be further subdivided into flavones, flavonols, isoflavones, flavanes, and flavanols. The biological activities of flavonoids are structure dependent and epidemiological studies support their role in human cancer prevention. Several flavonoids inhibit cancer development in animal models of chemical and UV carcinogenesis. However, at high dose some flavonoids themselves may also increase cancer incidence. Although flavonoids have been shown to inhibit cancer cell growth in vitro, the ability of flavonoids to limit cancer progression is limited in animal studies. A potential application is the possible synergisticaction of flavonoids with chemotherapy agents. Molecularly, flavonoids have antioxidant properties and can further enhance the antioxidant protein activities in cells and in animals. Isoflavones and some other flavonoids have weak affinity for the estrogen receptor. Neonatal exposure of animals to isoflavonoids affects the development of reproductive organs, an observation that opens the possibility of using isoflavonoids in the prevention of cancers of the reproductive system. Some growth-inhibiting flavonoids also bind to the low-affinity type II estrogen binding sites, but the biochemical identity of type II sites is unknown.

Fiber intake is critical for optimal health. This review covers the anti-inflammatory roles of fibers using results from human epidemiological observations, clinical trials, and animal studies. Fiber has body weight-related anti-inflammatory activity. With its lower energy density, a diet high in fiber has been linked to lower body weight, alleviating obesity-induced chronic inflammation evidenced by reduced amounts of inflammatory markers in human and animal studies. Body weight-unrelated anti-inflammatory activity of fiber has also been extensively studied in animal models in which the type and amount of fiber intake can be closely monitored. Fermentable fructose-, glucose-, and galactose-based fibers as well as mixed fibers have shown systemic and local intestinal anti-inflammatory activities when plasma inflammatory markers and tissue inflammation were examined. Similar anti-inflammatory activities have also been demonstrated in some human studies that controlled total fiber intake. The anti-inflammatory activities of synbiotics (probiotics plus fiber) were reviewed as well, but there was no convincing evidence indicating higher efficacy of synbiotics compared with that of fiber alone. Adverse effects have not been observed with the amount of fiber intake or supplementation used in studies, although patients with Crohn's disease may be more sensitive to inulin intake. Several possible mechanisms that may mediate the body weight-unrelated anti-inflammatory activity of fibers are discussed based on the in vitro and in vivo evidence. Fermentable fibers are known to affect the intestinal microbiome. The immunomodulatory role of the intestinal microbiome and/or microbial metabolites could contribute to the systemic and local anti-inflammatory activities of fibers.

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Human sodium-dependent vitamin C transporters, SVCT1 and SVCT2, share 66% sequence identity yet localize in the apical and basolateral membranes of epithelial cells, respectively. This pair thus serves as a model for studying multipass membrane protein targeting. Domain swaps, deletions, insertions, and point mutations were performed on EGFP-tagged hSVCT1 and hSVCT2 plasmids. Mutant proteins stably expressed in MDCK cells were analyzed by confocal microscopy and Transwell ascorbate transport assays. These studies identified an SVCT2 basolateral targeting sequence (BTS) in the N-terminus, which is conserved among mammalian SVCT2 forms. The less conserved N-terminus of SVCT1 is not required for apical localization. The destruction of SVCT2 BTS led to apical localization of the protein in a manner independent of the C-terminal sequence. A C-terminal sequence present in both SVCTs appears to be required for plasma membrane incorporation and retention as its deletion led to an increased level of intracellular appearance of both apically and basolaterally targeted SVCTs in the absence or presence of BTS. Nevertheless, all C-terminal deletion mutants showed preferential apical transport activity, suggesting a greater importance of this sequence for basolateral targeting. Our results collectively suggested a default apical targeting of SVCT, which is consistent with the evolution-based prediction. The SVCT sorting model with a hierarchal contribution of N- and C-terminal sequences was compared to the observations made for other multipass membrane proteins. The involvement of both intracellularly localized termini of multipass membrane proteins in the sorting pathway suggests a more complex sorting mechanism compared to that for single-pass proteins.