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

从转运体和屏障功能的角度研究了外源药物在肠上皮细胞单层中的转运机制。采用体外培养的肠上皮细胞模型，研究了参与外源药物外排的p -糖蛋白（P-gp）和参与细胞解毒的牛磺酸转运蛋白（Tau-TP）的特性。首先利用人肠上皮Caco-2细胞建立了评价这些转运蛋白活性的方法。研究了外源因素和食物因素对P-gp和Tau-TP活性的影响。三丁基锡（TBT）是一种内分泌干扰化学物质，对Caco-2细胞有毒性，但长期使用TBT可观察到P-gp的上调。这种上调伴随着mRNA水平的升高。渗透胁迫和细胞因子刺激可上调Tau-TP，但外源处理对其影响不显著。研究了食物因素对这些转运蛋白的长期和短期影响。包括苦瓜提取物在内的蔬菜提取物明显抑制P-gp的活性。从黑草提取物中分离纯化了活性物质。该材料的表征目前正在进行中。芝麻提取物对Tau-TP有抑制作用，抑制物质为溶血磷脂酰胆碱。并对这种抑制的可能机制进行了研究。

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.