Wogonin effects on the efflux transporters BCRP and MRP2, explain its effectiveness in ulcerative colitis: implications for metabolic and transport interactions.

Wogonin is a flavonoid with efficacy in ulcerative colitis (UC), while the mechanism of its action remains to be fully elucidated. Previous research has indicated that the activation of the triple recycling pathway significantly enhances the bioavailability of flavonoids. The efflux transporters, BCRP and MRP2 are critical regulatory molecules within the enterohepatic triple recycling pathways. Therefore, we investigated the regulatory impact of wogonin on BCRP and MRP2, as well as the roles of these transporters in wogonin's therapeutic efficacy in UC. Using dextran sulfate sodium (DSS)-induced UC model, we found that the anti-UC efficacy of wogonin was diminished in Bcrp-Mrp2 mice compared to wild-type (WT) mice. In these knockout mice, the content of wogonin was increased in the plasma but decreased in the colon tissues, suggesting that deficiencies in BCRP and MRP2 hinder the efflux of wogonin, resulting in elevated contents in the plasma. Moreover, in vitro results showed that after knockout of BCRP and MRP2, the concentration of wogonin increased and its UGT metabolite wogonoside, decreased in cells and mitochondria. This indicates that inhibiting efflux transporters suppresses cellular and mitochondrial glucuronidation metabolism. Interestingly, proteomic sequencing of mitochondrial subcellular organelles revealed that wogonin exhibited anti-UC effects by inhibiting afamin (AFM), with these effects modulated by BCRP and MRP2. These findings not only suggest a new mechanism for increasing the oral bioavailability of this flavonoid, but also provide a pharmacological foundation for the clinical use of wogonin in treating UC.