2,3,5,4'-Tetrahydroxy stilbene-2- Ο-β-D-glucoside, a mechanism-based inactivator of CYP2C19 and CYP3A4, potentiates hepatic protein adduction and hepatotoxicity induced by emodin in vivo

Chem Biol Interact. 2022 Nov 1:110234. doi: 10.1016/j.cbi.2022.110234. Online ahead of print.ABSTRACT2,3,5,4'-Tetrahydroxy stilbene-2-Ο-β-D-glucoside (TSG) and emodin (EMD) are two main components of Polygonum multiflorum Thunb. (PMT). Its root is widely used as herbal medicine and supplement. However, PMT-induced liver injury has drawn increasing attention. The purpose of this study was to investigate the interaction of TSG with EMD in the aspects of enzymology, pharmacokinetics, and hepatotoxicity. Co-administration with TSG increased internal exposure of EMD, EMD-derived hepatic protein adduction, and EMD-induced liver injury in mice. Mouse and human liver microsomal incubation study demonstrated that co-incubation with TSG decreased the formation of hydroxylation metabolites of EMD. Human recombinant cytochrome P450 enzyme incubation study showed that TSG induced time-, concentration-, NADPH-dependent and irreversible inhibition of CYP2C19 and CYP3A4. An epoxide metabolite derived from TSG was responsible for the observed enzyme inactivations. The findings allow us to better understand the mechanisms by which herbal processing detoxifies raw PMT.PMID:36332690 | DOI:10.1016/j.cbi.2022.110234
Source: Chemico-Biological Interactions - Category: Molecular Biology Authors: Source Type: research