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. 2012 Aug 8;17(8):9469-75.
doi: 10.3390/molecules17089469.

Demethylzeylasteral exhibits strong inhibition towards UDP-glucuronosyltransferase (UGT) 1A6 and 2B7

Jin-Wen Zhao  1 , Gui-Hua Wang, Min Chen, Lian-Hua Cheng, Xiao-Qi Ji
Affiliations

Demethylzeylasteral exhibits strong inhibition towards UDP-glucuronosyltransferase (UGT) 1A6 and 2B7

Jin-Wen Zhao et al. Molecules. .

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.

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Figures

Figure 1
Figure 1
The structure of demethylzeylasteral.
Figure 2
Figure 2
Inhibition kinetic analysis of demethylzeylasteral towards recombinant UGT1A6-catalyzed 4-MU glucuronidation. (A) Demethylzeylasteral showed dose-dependent inhibition towards UGT1A6; (B) Dixon plot of demethylzeylasteral inhibition towards UGT1A6-catalyzed 4-MU glucuronidation; (C) Lineweaver-Burk plot of demethylzeylasteral inhibition towards UGT1A6-catalyzed 4-MU glucuronidation; (D) Second plot using slope (obtained from Lineweaver-Burk plot) vs. the concentration of demethylzeylasteral.
Figure 3
Figure 3
Inhibition kinetic analysis of demethylzeylasteral towards recombinant UGT2B7-catalyzed 4-MU glucuronidation. (A) Demethylzeylasteral showed dose-dependent inhibition towards UGT2B7; (B) Dixon plot of demethylzeylasteral inhibition towards UGT2B7-catalyzed 4-MU glucuronidation; (C) Lineweaver-Burk plot of demethylzeylasteral inhibition towards UGT2B7-catalyzed 4-MU glucuronidation; (D) Second plot using slope (obtained from Lineweaver-Burk plot) vs. the concentration of demethylzeylasteral.
See this image and copyright information in PMC

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