Various non-digestible saccharides increase intracellular calcium ion concentration in rat small-intestinal enterocytes
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We have previously shown that non-digestible saccharides (NDS) stimulate intestinal Ca absorption via tight junctions. However, the cellular mechanisms activated by the NDS are not yet known. We investigated the effects of four NDS, difructose anhydride (DFA) III, DFAIV, fructo-oligosaccharides, and maltitol, on intracellular Ca signalling in isolated rat small-intestinal enterocytes. The changes in intracellular Ca(2+) concentration were measured before and after the addition of capric acid (7.5 or 15 mmol/l, a positive control), glycerol, or each NDS (1 or 10 mmol/l) to fura-2-loaded enterocytes. Treatment with capric acid or each NDS caused an immediate and dose-dependent rise in intracellular Ca(2+) concentration. Mechanical and osmotic stimulation achieved by adding glycerol had no effect on intracellular Ca(2+) concentration. The intracellular Ca(2+) concentration in enterocytes treated with DFAIII and fructo-oligosaccharides reached a peak level at about 30 s after stimulation, but those treated with DFAIV and maltitol showed further increases after the initial rapid rise. The maximum change in intracellular Ca(2+) concentration obtained by the application of maltitol was higher than that of DFAIII at 10 mmol/l. These findings suggest that each of the four NDS directly stimulates rat enterocytes, and increases intracellular Ca(2+) concentration. Thus, molecular structure may be more important than the size of the NDS in the induction of Ca signalling in the cells.Keywords:
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Adaptation following small bowel resection (SBR) signals enterocyte proliferation and apoptosis. Because p53-induced p21 waf1/cip1 may be important for apoptosis in many cells, we hypothesized that these genes are required for increased enterocyte apoptosis during adaptation. Male C57BL/6 (wild-type) or p53-null mice underwent 50% proximal SBR or sham operation (bowel transection-reanastomosis). Adaptation (DNA-protein content, villus height-crypt depth, enterocyte proliferation), appearance of apoptotic bodies, and p53 and p21 waf1/cip1 protein expression were measured in the ileum after 5 days. Adaptation was equivalent after SBR in both wild-type and p53-null mice as monitored by significantly increased ileal DNA-protein content, villus height, and enterocyte proliferation. The number of crypt apoptotic bodies increased significantly after SBR evenly in both wild-type and p53-null mice. In the p53-null mice, SBR substantially induced the expression of p21 waf1/cip1 protein in villus enterocytes. The p53-independent induction of p21 waf1/cip1 may account for the similar intestinal response to SBR between wild-type and p53-null mice. Intestinal adaptation and increased enterocyte apoptosis following intestinal resection occur via a p53-independent mechanism.
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The mechanisms underlying the biosynthesis, intracellular transport, and sorting of proteins destined for extra- and intracellular use have been extensively studied in polarized epithelial cells during the last few years. Much of our understanding about these mechanisms arose from studies on the intracellular pathways taken by newly synthesized viral membrane glycoproteins in cultured epithelial cells (K. Simons and Fuller 1985, N.L. Simons et al. 1985). However, little information is available about the synthesis and transport of endogenous glycoproteins (Danielsen et al. 1984). To study these processes the intestinal epithelial cell (enterocyte) is an attractive model for a number of reasons.
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Due to the rapid turnover of the small intestinal epithelia, the rate at which enterocyte renewal occurs plays an important role in determining the level of drug-metabolizing enzymes in the gut wall. Current physiologically based pharmacokinetic (PBPK) models consider enzyme and enterocyte recovery as a lumped first-order rate. An assessment of enterocyte turnover would enable enzyme and enterocyte renewal to be modeled more mechanistically. A literature review together with statistical analysis was employed to establish enterocyte turnover in human and preclinical species. A total of 85 studies was identified reporting enterocyte turnover in 1602 subjects in six species. In mice, the geometric weighted combined mean (WX) enterocyte turnover was 2.81 ± 1.14 days (n = 169). In rats, the weighted arithmetic mean enterocyte turnover was determined to be 2.37 days (n = 501). Humans exhibited a geometric WX enterocyte turnover of 3.48 ± 1.55 days for the gastrointestinal epithelia (n = 265), displaying comparable turnover to that of cytochrome P450 enzymes in vitro (0.96-4.33 days). Statistical analysis indicated humans to display longer enterocyte turnover as compared with preclinical species. Extracted data were too sparse to support regional differences in small intestinal enterocyte turnover in humans despite being indicated in mice. The utilization of enterocyte turnover data, together with in vitro enzyme turnover in PBPK modeling, may improve the predictions of metabolic drug-drug interactions dependent on enzyme turnover (e.g., mechanism-based inhibition and enzyme induction) as well as absorption of nanoparticle delivery systems and intestinal metabolism in special populations exhibiting altered enterocyte turnover.
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Due to the rapid turnover of the small intestinal epithelia, the rate at which enterocyte renewal occurs plays an important role in determining the level of drug metabolising enzymes in the gut-wall. Current physiologically-based pharmacokinetic (PBPK) models consider enzyme and enterocyte recovery as a lumped first-order rate. An assessment of enterocyte turnover would enable enzyme and enterocyte renewal to be modelled more mechanistically. A literature review together with statistical analysis was employed in order to establish enterocyte turnover in human and pre-clinical species. A total of 85 studies were identified reporting enterocyte turnover in 1,602 subjects in six species. In mice, the weighted combined geometric mean (WX) enterocyte turnover was 2.81±1.14 days (n=169). In rats, the weighted arithmetic mean enterocyte turnover was determined to be 2.37 days (n=501). Human exhibited a WX enterocyte turnover of 3.48±1.55 days for the gastrointestinal (GI) epithelia (n=265), displaying comparable turnover to that of Cytochrome P450 enzymes in vitro (0.96-4.33 days). Statistical analysis indicated human to display longer enterocyte turnover as compared to pre-clinical species. Extracted data was too sparse to support regional differences in small intestinal enterocyte turnover in man despite being indicated in mouse. The utilisation of enterocyte turnover data, together with in vitro enzyme turnover in PBPK modelling may improve the predictions of metabolic DDIs dependent on enzyme turnover (e.g. mechanism-based inhibition and enzyme induction) as well as absorption of nanoparticle delivery systems and intestinal metabolism in special populations exhibiting altered enterocyte turnover.
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