Potential of herb-drug / herb interactions between substrates and inhibitors of UGTs derived from herbal medicines

Herbal medicines are widely used as alternative or complementary therapies worldwide to treat and prevent chronic diseases. However, herbal medicines coadministration with therapeutic drugs may cause dramatic clinical herb-drug/herb interactions (HDIs/HHIs) that may result in low drug efficacy or serious toxic reactions. Phase II metabolism enzyme UDP-glucuronosyltransferases (UGTs) play a significant detoxification role in vivo. Most drugs and non-drug xenobiotics undergo phase II metabolic transformations to be more polar compounds that are more easily excreted. Herbal medicines are a mixed and chemically varied group that includes flavonoids, stilbenes, coumarins, quinones, and terpenes, which are potential substrates and inhibitors of UGTs. Although increasing studies about glucuronidation metabolism and the inhibition toward UGTs of many herbal medicines have been reported, it is still difficult to determine which compounds from herbal medicines are substrates or inhibitors of UGTs. This article gives an overview of UGTs studies, which mainly focuses on glucuronidation of herbal constituents as substrates catalyzed by UGTs, potential herbal inhibitors for UGTs. We summarize the negative effects of UGT1A polymorphism and single nucleotide polymorphisms (SNPs), relevant clinical situations of HDIs/HHIs induced by inhibition of UGTs, and propose establishing classification criteria for inhibitors. Finally, we also discuss future research and strategic directions to advance the understanding of the potential HDIs/HHIs and suggest some additional studies revealing more information on UGT-mediated HDIs/HHIs.