Abstract
Celastrol, a quinone methide triterpene isolated from Tripterygium wilfordii Hook F., has various biochemical and pharmacological activities, and is now being developed as a promising anti-tumor agent. Inhibitory activity of compounds towards UDP-glucuronosyltransferase (UGT) is an important cause of clinical drug-drug interactions and herb-drug interactions. The aim of the present study is to investigate the inhibition of celastrol towards two important UDP-glucuronosyltransferase (UGT) isoforms UGT1A6 and UGT2B7. Recombinant UGT isoforms and non-specific substrate 4-methylumbelliferone (4-MU) were used. The results showed that celastrol strongly inhibited the UGT1A6 and 2B7-mediated 4-MU glucuronidation reaction, with 0.9 ± 0.1% and 1.8 ± 0.2% residual 4-MU glucuronidation activity at 100 μM of celastrol, respectively. Furthermore, inhibition kinetic study (Dixon plot and Lineweaver-Burk plot) demonstrated that celastrol noncompetitively inhibited the UGT1A1-mediated 4-MU glucuronidation, and competitively inhibited UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameters (Ki) were calculated to be 0.49 μM and 0.045 μM for UGT1A6 and UGT2B7, respectively. At the therapeutic concentration of celastrol for anti-tumor utilization, the possibility of celastrol-drug interaction and celastrol-containing herbs-drug interaction were strongly indicated. However, given the complicated nature of herbs, these results should be viewed with more caution.
Highlights
Tripterygium wilfordii Hook F. is an ivy-like vine, widely used in Traditional Chinese Medicine for hundreds of years to treat fever, chills, edema and carbuncles [1]
Celastrol (Figure 1), a quinone methide triterpene, is one of active components isolated from Tripterygium wilfordii Hook F. [2]
For metabolic enzymes inhibition-based herb-drug interactions, inhibition of cytochrome P450 (CYP) by herbal constituents has been widely investigated and regarded as a major reason, because CYPs are involved in the metabolism of most clinical drugs [10]
Summary
Tripterygium wilfordii Hook F. is an ivy-like vine, widely used in Traditional Chinese Medicine for hundreds of years to treat fever, chills, edema and carbuncles [1]. Herb-induced adverse effects are a major cause that limits the clinic utilization of herbal medicines. The metabolic behaviour of herbal components plays a key role in herbs’ adverse effects, including metabolic activation-induced herb toxicity and metabolic enzymes inhibition-based herb-drug interactions [9]. For metabolic enzymes inhibition-based herb-drug interactions, inhibition of cytochrome P450 (CYP) by herbal constituents has been widely investigated and regarded as a major reason, because CYPs are involved in the metabolism of most clinical drugs [10]. Many selective probe reactions of CYPs can be effectively utilized to investigate the inhibition of herbal constituents towards various CYP isoforms. These probe reactions have been employed to find many herbal ingredients strongly inhibiting CYP isoforms, including ginsenosides [11], corynoline [12], curcumenol [13], and flavonoids [14]
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