Dong De-Gang, Zhang Yao, Zhang Shu-Lan, Lv Jing, Guo En-Mian, Fang Zhong-Ze, Cao Yun-Feng
The Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
Pharmazie. 2014 Jan;69(1):60-3.
Bakuchiol is a promising anti-tumor candidate with resveratrol-like structure. The present study aims to evaluate the inhibition potential of bakuchiol towards UDP-glucuronosyltransferases (UGT) 1A isoforms. An in vitro incubation system using 4-methylumbelliferone (4-MU) glucuronidation was used to evaluate the inhibition capability of bakuchiol towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9 and 1A10. The glucuronidation of trifluoperazine (TFP) was employed as the probe reaction to determine bakuchiol's inhibition towards UGT1A4. At 1 microM and 10 microM of bakuchiol, no or weak inhibition was observed for all the tested UGT1A isoforms. At 100 microM of bakuchiol, the activity of UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9 and 1A10 was inhibited by -46.2%, 74.7%, 17.8%, 98.7%, 70.4%, 99.2%, 75.8%, and 93.3%, respectively. Further inhibition kinetic behaviour was determined for UGT1A6, 1A8, and 1A10. Both Dixon plot and Lineweaver-Burk plot showed the noncompetitive inhibition of bakuchiol towards all these three UGT isoforms. The inhibition kinetic parameters (Ki) were calculated to be 5.3, 1.8, and 92.6 microM for UGT1A6, 1A8, and 1A10, respectively. In combination with the in vivo exposure of bakuchiol, the high possibility of in vivo inhibition of UGT1A6 and 1A8 was predicted. However, relatively low possibility of in vivo inhibition towards UGT1A10 was predicted due to lower in vivo concentration of bakuchiol than its inhibition parameter (Ki). All these information will be helpful for the R&D of bakuchiol as a promising anti-tumor drug.
补骨脂酚是一种具有白藜芦醇样结构的有前景的抗肿瘤候选物。本研究旨在评估补骨脂酚对尿苷二磷酸葡萄糖醛酸基转移酶（UGT）1A同工型的抑制潜力。使用4-甲基伞形酮（4-MU）葡萄糖醛酸化的体外孵育系统来评估补骨脂酚对UGT1A1、1A3、1A6、1A7、1A8、1A9和1A10的抑制能力。使用三氟拉嗪（TFP）的葡萄糖醛酸化作为探针反应来确定补骨脂酚对UGT1A4的抑制作用。在补骨脂酚浓度为1微摩尔/升和10微摩尔/升时，未观察到对所有测试的UGT1A同工型有抑制作用或仅有微弱抑制。在补骨脂酚浓度为100微摩尔/升时，UGT1A1、1A3、1A4、1A6、1A7、1A8、1A9和1A10的活性分别被抑制了46.2%、74.7%、17.8%、98.7%、70.4%、99.2%、75.8%和93.3%。对UGT1A6、1A8和1A10进一步测定了抑制动力学行为。迪克森图和林-贝氏图均显示补骨脂酚对所有这三种UGT同工型均为非竞争性抑制。计算得出对UGT1A6、1A8和1A10的抑制动力学参数（Ki）分别为5.3、1.8和92.6微摩尔/升。结合补骨脂酚的体内暴露情况，预测其在体内抑制UGT1A6和1A8的可能性很高。然而，由于补骨脂酚的体内浓度低于其抑制参数（Ki），因此预测其在体内抑制UGT1A10的可能性相对较低。所有这些信息将有助于补骨脂酚作为一种有前景的抗肿瘤药物的研发。
