全面反应表型分析普萘洛尔和 4-羟普萘洛尔与人类 UGT1 和 UGT2 酶家族的 19 种酶。

Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families.

机构信息

Pharmaceutical and Medicinal Chemistry (Pharmaceutical Analyses), Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.

Pharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.

出版信息

Int J Mol Sci. 2022 Jul 5;23(13):7476. doi: 10.3390/ijms23137476.

Propranolol is a competitive non-selective beta-receptor antagonist that is available on the market as a racemic mixture. In the present study, glucuronidation of propranolol and its equipotent phase I metabolite 4-hydroxypropranolol by all 19 members of the human UGT1 and UGT2 families was monitored. UGT1A7, UGT1A9, UGT1A10 and UGT2A1 were found to glucuronidate propranolol, with UGT1A7, UGT1A9 and UGT2A1 mainly acting on ()-propranolol, while UGT1A10 displays the opposite stereoselectivity. UGT1A7, UGT1A9 and UGT2A1 were also found to glucuronidate 4-hydroxypropranolol. In contrast to propranolol, 4-hydroxypropranolol was found to be glucuronidated by UGT1A8 but not by UGT1A10. Additional biotransformations with 4-methoxypropanolol demonstrated different regioselectivities of these UGTs with respect to the aliphatic and aromatic hydroxy groups of the substrate. Modeling and molecular docking studies were performed to explain the stereoselective glucuronidation of the substrates under study.

普萘洛尔是一种竞争性非选择性β受体拮抗剂，以外消旋混合物的形式在市场上销售。在本研究中，监测了人类 UGT1 和 UGT2 家族的 19 个成员对普萘洛尔及其等效力的 I 期代谢物 4-羟基普萘洛尔的葡萄糖醛酸化。发现 UGT1A7、UGT1A9、UGT1A10 和 UGT2A1 可使普萘洛尔葡萄糖醛酸化，其中 UGT1A7、UGT1A9 和 UGT2A1 主要作用于（）-普萘洛尔，而 UGT1A10 则表现出相反的立体选择性。还发现 UGT1A7、UGT1A9 和 UGT2A1 可使 4-羟基普萘洛尔葡萄糖醛酸化。与普萘洛尔不同，发现 4-羟基普萘洛尔可被 UGT1A8 但不能被 UGT1A10 葡萄糖醛酸化。用 4-甲氧基丙醇进行其他生物转化，证明了这些 UGT 对底物的脂肪族和芳香族羟基的区域选择性不同。进行了建模和分子对接研究，以解释研究中底物的立体选择性葡萄糖醛酸化。