Molecular mechanisms of the transporters involved in the intestinal cell responses to xenobiotics and regulation of the transporters by food factors

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Mechanisms for the transport of xenobiotics across the intestinal epithelial cell monolayers were investigated from the viewpoints of transporter and barrier functions. Characteristics of P-glycoprotein (P-gp) which is involved in the efflux of xenobiotics, and those of taurine transporter (Tau-TP) which is involved in the detoxification of cells were studied by using a cultured intestinal epithelial cell model. Methods to evaluate these transporter activities were first established by using a human intestinal epithelial Caco-2 cells. Effects of external factors such as xenobiotics and food factors on the activities of P-gp and Tau-TP were then studied. Tributyltin(TBT), an endocrine disrupting chemical, was toxic to Caco-2 cells, but up-regulation of P-gp by a long-term treatment with TBT was observed. This up-regulation was accompanied by the increase in the mRNA level. Tau-TP was up-regulated by osmotic stresses and cytokine stimulation, but was not significantly influenced by xenobiotic treatment. Long-term and short-term effects of food factors on these transporters were investigated. Vegetable extracts including the extract of bitter melon (Nigauri) markedly inhibited the activity of P-gp. The active substances were isolated and purified from the Nigauri extract. Characterization of the material is now in progress. Sesame seeds extract inhibited the Tau-TP, and the inhibitory substance was identified as lysophosphatidylcholine. The possible mechanisms for this inhibition was also studied.