相对活动与相对表达因子 (RAF与REF) 的比较,用于预测使用复合性UGTs的葡萄糖化中介药物清除
Sandhya Subash1, Deepak Ahire1, Mitesh Patel2
1Department of Pharmaceutical Sciences, Washington State University (WSU), Spokane, WA, 99202, USA.
Pharmaceutical research
|August 6, 2024
概括
预测葡萄化需要了解UDP-葡萄基转移酶 (UGT) 酶活性. 这项研究发现重组UGTs (rUGTs) 具有较差和可变的特异活性,影响葡萄糖化 (fgluc) 预测的定量分数.
科学领域:
- 药物代谢和药理动力学
- 酶动力学 酶动力学
- 生物技术是生物技术.
背景情况:
- 预测单个UDP-glucuronosyltransferase (UGT) 酶的葡萄糖化 (fgluc) 的定量分数对于药物开发至关重要.
- 由于缺乏选择性抑制剂和重组UGT系统 (rUGTs) 不一致的活性,存在挑战.
研究的目的:
- 为了比较相对表达因子 (REF) 与相对活动因子 (RAF),用于预测fgluc.
- 使用rUGT数据对人类肝脏和肠道显微体 (HLM和HIM) 评估REF和RAF的实用性.
主要方法:
- REF标量是从11个UGT酶的蛋白质组学数据中得出的.
- 通过在rUGT和微体中测量活动,用选择性的UGT探头基板来计算RAF.
- 蛋白质正常化活性因子 (pnAF) 是通过将UGT活性与蛋白质丰度进行校正来生成的.
主要成果:
- REF值在0.02至1.75之间;RAF值在0.1至274之间.
- pnAF值通常是5到80倍,除了UGT2B4 (~180倍) 和UGT2B15 (>1000倍) 的例外.
- rUGTs的不同特定活动影响了fgluc的预测.
结论:
- 在同等蛋白质量下,复合UGT酶活性明显低于微粒中的水平.
- rUGTs (蛋白质每 pmol) 的低和可变的特异活性需要在fgluc缩放中仔细考虑.
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