State Key Laboratory of Natural Products and Functions, Ministry of Education, China Pharmaceutical University, Nanjing, P.R. China.
Drug Metab Pharmacokinet. 2012;27(6):579-85. doi: 10.2133/dmpk.dmpk-12-rg-023. Epub 2012 Apr 27.
Glucuronidation is an important pathway in the elimination of salvianolic acid A (Sal A); however the mechanism of UDP-glucuronosyltransferases (UGTs) in this process remains to be investigated. In this study, the kinetics of Sal A glucuronidation by pooled human liver microsomes (HLMs), pooled human intestinal microsomes (HIMs) and 12 recombinant UGT isozymes were investigated. The glucuronidation of Sal A can be shown both in HLMs and HIMs with K(m) values of 39.84 ± 3.76 and 54.04 ± 4.36 µM, respectively. Among the 12 human UGTs investigated, UGT1A1 and UGT1A9 were the major isoforms that catalyzed the glucuronidation of Sal A (K(m) values of 29.72 ± 2.20 and 24.40 ± 2.60 µM). UGT1A9 showed the highest affinity of Sal A glucuronidation. Furthermore, a significant correlation between Sal A glucuronidation and propofol glucuronidation (a typical UGT1A9 substrate) was observed. The chemical inhibition study showed that the IC(50) for phenylbutazone inhibition of Sal A glucuronidation was 50.3 ± 4.3 and 39.4 ± 2.9 µM by HLMs and UGT1A9, respectively. Mefenamic acid inhibited Sal A glucuronidation in UGT1A1 and HLMs with IC(50) values of >200 and 12.4 ± 2.2 µM, respectively.
葡萄糖醛酸化是丹参酸 A（Sal A）消除的重要途径；然而，该过程中尿苷二磷酸葡萄糖醛酸转移酶（UGTs）的机制仍有待研究。在这项研究中，研究了人肝微粒体（HLMs）、人肠微粒体（HIMs）和 12 种重组 UGT 同工酶对 Sal A 葡萄糖醛酸化的动力学。Sal A 的葡萄糖醛酸化在 HLMs 和 HIMs 中均能显示，其 K(m)值分别为 39.84 ± 3.76 和 54.04 ± 4.36 µM。在所研究的 12 种人 UGT 中，UGT1A1 和 UGT1A9 是催化 Sal A 葡萄糖醛酸化的主要同工酶（K(m)值分别为 29.72 ± 2.20 和 24.40 ± 2.60 µM）。UGT1A9 对 Sal A 葡萄糖醛酸化的亲和力最高。此外，Sal A 葡萄糖醛酸化与丙泊酚葡萄糖醛酸化（一种典型的 UGT1A9 底物）之间存在显著相关性。化学抑制研究表明，HLMs 和 UGT1A9 中苯丁唑酮抑制 Sal A 葡萄糖醛酸化的 IC(50)值分别为 50.3 ± 4.3 和 39.4 ± 2.9 µM。甲芬那酸抑制 UGT1A1 和 HLMs 中的 Sal A 葡萄糖醛酸化，IC(50)值分别为>200 和 12.4 ± 2.2 µM。
Zotero 插件