Bile acid hydrophobicity is correlated with induction of apoptosis and/or growth arrest in HCT116 cells
Bile acid hydrophobicity is correlated with induction of apoptosis and/or growth arrest in HCT116 cells
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DOI：
10.1042/0264-6021:3560481
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发表时间：
2001-06-01
影响因子：
4.1
通讯作者：
Martinez, JD
中科院分区：
文献类型：
--
作者：
Powell, AA;LaRue, JM;Martinez, JD
长期以来，粪便胆汁酸与结肠癌有关;高度疏水性胆汁酸，诱导细胞凋亡，与结肠肿瘤的促进有关。中等疏水性的化学预防剂熊去氧胆酸（UDCA）不会诱导细胞凋亡;相反，它会导致结肠源性肿瘤细胞停止生长。为了研究胆汁酸疏水性和生物活性之间的关系，我们检测了26种胆汁酸诱导细胞凋亡或改变细胞生长的能力。我们发现，胆汁酸诱导细胞凋亡或生长停滞的速度和程度与其相对疏水性相关。在所测试的胆汁酸中，只有脱氧胆酸（DCA）和鹅脱氧胆酸（测试的最疏水的胆汁酸）可以在不到12小时的时间内诱导人结肠癌细胞系HCT 116的凋亡。中度疏水性胆汁酸hyoDCA、lagoDCA、norDCA、homoUDCA和isoUDCA在12 h时诱导生长停滞，但更长时间的孵育导致细胞凋亡。甘氨酸或牛磺酸的共轭胆汁酸的相对疏水性降低，消除了我们的测定中的生物活性。此外，我们测试了这些胆汁酸的一个子集的跨细胞膜易位的能力。当将C-14标记和H-3标记的DCA、UDCA和lagoDCA加入到细胞培养物中时，我们发现结肠细胞的吸收量很小，而肝细胞的吸收量要高得多。这些实验表明，疏水性是胆汁酸所表现出的生物活性的重要决定因素，但在我们的条件下，这些活动与细胞摄取无关。
Faecal bile acids have long been associated with colon cancer; highly hydrophobic bile acids, which induce apoptosis, have been implicated in the promotion of colon tumours. The moderately hydrophobic chemopreventive agent ursodeoxycholic acid (UDCA) does not induce apoptosis; rather, it causes colon-derived tumour cells to arrest their growth. To investigate the relationship between bile acid hydrophobicity and biological activity we examined 26 bile acids for their capacity to induce apoptosis or alter cell growth. We found that the rapidity with which, and the degree to which, bile acids could induce apoptosis or growth arrest was correlated with their relative hydrophobicities. Of the bile acids tested, only deoxycholic acid (DCA) and chenodeoxycholic acid, the most hydrophobic bile acids tested, could induce apoptosis in less than 12 h in the human colon cancer cell line HCT116. The moderately hydrophobic bile acids hyoDCA, lagoDCA, norDCA, homoUDCA and isoUDCA induced growth arrest at 12 h but longer incubations resulted in apoptosis. Conjugation of glycine or taurine to the bile acids decreased relative hydrophobicity and eliminated biological activity in our assays. In addition, we tested a subset of these bile acids for their ability to translocate across cell membranes. When C-14-labelled and H-3-labelled DCA, UDCA and lagoDCA were added to cell cultures, we found only minimal uptake by colon cells, whereas hepatocytes had considerably higher absorption. These experiments suggest that hydrophobicity is an important determinant of the biological activity exhibited by bile acids but that under our conditions these activities are not correlated with cellular uptake.