Demethylzeylasteral Exhibits Strong Inhibition towards UDP-Glucuronosyltransferase (UGT) 1A6 and 2B7

Abstract

Inhibition of UDP-glucuronosyltransferase (UGT) isoforms can result in severe clinical results, including clinical drug-drug interactions (DDI) and metabolic disorders of endogenous substances. The present study aims to investigate the inhibition of demethylzeylasteral (an important active component isolated from Tripterygium wilfordii Hook F.) towards three important UGT isoforms UGT1A6, UGT1A9 and UGT2B7. The results showed that 100 μM of demethylzeylasteral exhibited strong inhibition towards UGT1A6 and UGT2B7, with negligible influence towards UGT1A9. Furthermore, Dixon and Lineweaver-Burk plots showed the inhibition of UGT1A6 and UGT2B7 by demethylzeylasteral was best fit to competitive inhibition, and the inhibition kinetic parameters (Ki) were calculated to be 0.6 μM and 17.3 μM for UGT1A6 and UGT2B7, respectively. This kind of inhibitory effect need much attention when demethylzeylasteral and demethylzeyasteral-containing herbs (e.g., Tripterygium wilfordii Hook F.) were co-administered with the drugs mainly undergoing UGT1A6, UGT2B7-catalyzed metabolism. However, when extrapolating the in vivo clinical results using our present in vitro data, many complex factors might affect final results, including the contribution of UGT1A6 and UGT2B7 to the metabolism of compounds, and the herbal or patients’ factors affecting the in vivo concentration of demethylzeylasteral.

SOX1 promotes differentiation of nasopharyngeal carcinoma cells by activating retinoid metabolic pathway

“…T-96 was reported to inhibit UGT1A6 (Ki = 0.6 μM) and UGT2B7 (Ki = 17.3 μM) 38 . It was originally used as an immunosuppressive agent, which significantly inhibited the activation of NF-κB 39 .…”

Network Pharmacology-Based Prediction and Verification of Qingluo Tongbi Formula to Reduce Liver Toxicity of Tripterygium wilfordii via UGT2B7 in Endoplasmic Reticulum

“…Studies on TWHF toxicity have focused mainly on phase II metabolic enzymes. Zhao et al [21] demonstrated that demethylzeylasteral, an active ingredient of TWHF, strongly inhibits UGT1A6 and UGT2B7 in inhibitory studies on UGT1A6, UGT1A9, and UGT2B7. This observation indicates the need to monitor the potential clinical interactions between demethylzeylasteral-containing herbs and clinical drugs that mainly undergo UGT1A6-and UGT2B7-catalyzed metabolism.…”

Validated assay for the evaluation of multiple glucuronidation activities in human liver microsomes via liquid chromatography-tandem mass spectrometry

“…6,13 Moreover, AZT is primarily catalyzed by UGT2B7; 14 meanwhile, 4-MU, a nonspe-cic probe substrate for UGT isoforms, is oen used to investigate multiple UGT activities. 7,15 Therefore, estradiol, propofol, AZT, and 4-MU were used to evaluate the multiple glucuronidation activities in HLMs for this experiment.…”