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异物在肠上皮细胞单层中的转运机制。用培养的肠上皮细胞模型研究了参与外源物质外流的P-糖蛋白(P-gp)和参与细胞解毒的牛磺酸转运体(Tau-TP)的特性。方法首先利用人肠上皮细胞Caco-2建立评价转运蛋白活性的方法。研究了外源物质和食物等外界因素对P-gp和Tau-TP活性的影响。三丁基锡(TBT)是一种内分泌干扰物，对Caco-2细胞有毒性作用，但长期作用可上调P-gp的表达。这种上调伴随着信使核糖核酸水平的升高。Tau-TP被渗透胁迫和细胞因子刺激上调，但不受异种生物处理的显著影响。研究了食物因素对这些转运蛋白的长期和短期影响。苦瓜(Nigauri)提取物对P-gp活性有明显的抑制作用。活性物质是从黑果提取物中分离纯化出来的。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。并对这种抑制作用的可能机制进行了探讨。

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.