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.
Highlights
Tripterygium wilfordii Hook F., commonly known in China as Lei-Gong-Teng, has been used to treat rheumatoid arthritis, chronic nephritis, ankylosing spondylitis and various skin diseases [1,2,3].Demethylzeylasteral (Figure 1), the active component isolated from Tripterygium wilfordii Hook F., has been demonstrated to exhibit some pharmacological activity, including immunosuppressive effects [4].Herb-drug interactions have become a challenging problem in clinical application of herbs, and one of the major reasons is the influence of herbs on the pharmacokinetic behaviour of drugs [5]
Other herbal components exerting inhibition towards cytochrome P450s (CYPs) isoforms contain the active components isolated from Ginkgo biloba [7], flavonoids [8], and Danshen's constituents [9]
The aim of the present study is to investigate the inhibition of demethylzeylasteral towards three important UGT isoforms UGT1A6, UGT1A9 and UGT2B7
Summary
Tripterygium wilfordii Hook F., commonly known in China as Lei-Gong-Teng, has been used to treat rheumatoid arthritis, chronic nephritis, ankylosing spondylitis and various skin diseases [1,2,3]. UDP-glucuronosyltransferases (UGTs) are the most important enzymes catalyzing the conjugation of various xenobiotics and endogenous substances, which accounts for >35% of all phase II drug metabolism [10]. Inhibition of UGTs-catalyzed glucuronidation might induce severe clinical results, including drug-drug interactions and metabolic disorders of endogenous substances. For investigation of compounds’ inhibition towards CYP isoforms, many specific probe substrates and human liver microsomes have been developed. When evaluating the inhibition of compounds towards UGT isoforms, the non-specific substrate 4-MU was the routine probe, and the recombinant UGT isoforms were commonly used as enzyme sources [13,14]. The aim of the present study is to investigate the inhibition of demethylzeylasteral towards three important UGT isoforms UGT1A6, UGT1A9 and UGT2B7. The detailed inhibition kinetic type and parameters were determined
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
