Interactions of oleanane pentacyclic triterpenoids with human organic anion transporting polypeptide 1B1 and 1B3

Yiqing Tian; Xue Wang; Yajuan Bi; Xuejuan Li; Yang Zhang; Yao Yao; Mingzhe Zhang; Tong Xu; Youheng Zhang; Chunshan Gui; Weihua Zhang; Chunze Zhang; Heshui Yu; Youcai Zhang

doi:10.1016/j.tiv.2024.105842

Interactions of oleanane pentacyclic triterpenoids with human organic anion transporting polypeptide 1B1 and 1B3

Toxicol In Vitro. 2024 May 16:98:105842. doi: 10.1016/j.tiv.2024.105842. Online ahead of print.

Authors

Yiqing Tian¹, Xue Wang², Yajuan Bi¹, Xuejuan Li³, Yang Zhang³, Yao Yao⁴, Mingzhe Zhang¹, Tong Xu¹, Youheng Zhang⁵, Chunshan Gui⁶, Weihua Zhang⁷, Chunze Zhang⁴, Heshui Yu⁸, Youcai Zhang⁹

Affiliations

¹ School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
² Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
³ College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
⁴ Department of Colorectal Surgery, Tianjin, Union Medical Center, Tianjin 30021, China.
⁵ Department of General Practice, Nanjing Tianyinshan Hospital, Jiangsu 211100, China.
⁶ College of Pharmaceutical Sciences, Soochow University, Jiangsu 215123, China.
⁷ Tianjin Haihe Hospital, Tianjin 300051, China.
⁸ College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China. Electronic address: hs_yu08@163.com.
⁹ School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China. Electronic address: youcai.zhang@tju.edu.cn.

PMID: 38761881
DOI: 10.1016/j.tiv.2024.105842

Abstract

Oleanane pentacyclic triterpenoids have been widely used in clinical practice. However, studies on their interactions with hepatic transporters remain limited. In this study, we systematically investigated the inhibitory effects of 14 oleanane pentacyclic triterpenoids on organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), two liver-specific uptake transporters. Through fluorescence-based cellular uptake assays, we identified three potent OATP1B1 inhibitors (saikosaponin B1, saikosaponin A and 18β-glycyrrhetinic acid) and five potent OATP1B3 inhibitors (echinocystic acid, 3-oxo-16α-hydroxy-olean-12-en-28β-oic acid, chikusetsu saponin IVa, saikosaponin B1 and 18β-glycyrrhetinic acid). Structural analysis revealed that free oleanane triterpenoids inhibited OATP1B1/1B3 more potently than triterpene glycosides. Despite their similar structures, 18β-glycyrrhetinic acid exhibited much stronger inhibition on OATP1B1/1B3 than 18α-glycyrrhetinic acid, while both were substrates of OATP1B3. Interestingly, OATP1B3 overexpression significantly increased reactive oxygen species (ROS) levels in HepG2 cells after treatment with 18β-glycyrrhetinic acid. To conclude, this study highlights the potential interactions of oleanane pentacyclic triterpenoids with OATP1B1/1B3, and provides novel insights into the anti-cancer activity of 18β-glycyrrhetinic acid.

Keywords: Drug-drug interactions; Oleanane pentacyclic triterpenoids; Organic anion transporting polypeptide.