Triptolide Affects the Function of Hepatocellular Drug Uptake Transporter Organic Anion Transporting Polypeptide 1B1 Through the Suppression of SGK1

Organic anion transporting polypeptide 1B1 (OATP1B1) is specifically expressed at the basolateral membrane of human liver cells and transports a wide range of endogenous compounds, toxins, and drugs, making it a crucial factor in determining the pharmacokinetics of many clinically important medications. Triptergium wilfordii Hook. f. (TWHF) is a traditional Chinese medicine known for its long history of therapeutic effects. A previous study conducted in our laboratory found that major components of TWHF, including wilforine (WFR), wilforgine (WFG), celastrol (CL), and triptolide (TPL), directly suppressed the function of OATP1B1. In the current study, we investigated the long-term (24 h) effects of these TWHF components on the transporter. It was found that TPL was the most potent compound exhibiting inhibitory effects. Mechanistically, TPL accelerated the degradation of OATP1B1, which is likely mediated by serum and glucocorticoid-induced kinase 1 (SGK1). TPL downregulated the mRNA expression of SGK1 and reduced the nuclear accumulation of nuclear factor kappa B (NFκB). Further analysis of the upstream sequence of SGK1 identified three potential binding sites for NFκB. Both luciferase activity assays and chromatin immunoprecipitation (ChIP) analyses confirmed the binding of NFκB to two specific sites located at −1015 bp~−1006 bp and −319 bp~−310 bp.