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Ethnopharmacological Relevance: Spica prunellae (SP) is a well-known traditional Chinese medicinal herb with properties of antihypertensive, antihyperglycemic, antiviral, anti-inflammatory, and antitumor activities. This herb is also popularly consumed as a food additive in some drinks or other food forms for treating pyreticosis. Rosmarinic acid (RA) is the marker compound from SP, which possesses anti-oxidative and anti-inflammatory functions., Aim of the Study: This study aims to investigate the regulatory effect of the water extract of SP (WESP) and RA on efflux transports (ETs), including P-glycoprotein (p-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) in HepG2 cell line. Results would provide beneficial information for the proper application of SP in clinics., Materials and Methods: HepG2 cells were treated with different doses of the tested drugs for 24 or 96h. MTT assay was used to examine cell viability. The protein and mRNA levels of the ETs were measured by using Western blot and real-time PCR, respectively. Reporter assay was used to study the antioxidant response element (ARE)-luciferin activity by using HepG2-C8 cells, which were generated by transfecting plasmid containing ARE-luciferin gene into HepG2 cells. The transport activities of ETs were tested by using substrate probes., Results: WESP significantly (p<0.05) increased the expression of ETs in a dose-dependent manner. The increase caused by WESP was stronger than RA alone. Both WESP and RA promoted the translocation of nuclear factor E2-related factor-2 (Nrf2) from cytoplasm to the nucleus as well as significantly (p<0.05) enhanced the ARE-luciferin activity. WESP and RA also enhanced the efflux activity of P-gp and MRP2, accompanied by marked increase (p<0.05) in the intracellular ATP levels., Conclusions: WESP could significantly induce the expression of ETs through the activation of Nrf2-mediated signaling pathway in HepG2 cells. RA could be one of the active compounds responsible for the induction. WESP and RA also enhanced the efflux activity of P-gp and MRP2, and the increased intracellular ATP levels were likely involved in this induction. Results of this study provide a better understanding of the regulation of SP on ETs and the underlying molecular mechanism. Results indicated that potential drug-drug interactions may exist when SP is co-administered with other substrate drugs that are transported via the ETs, especially P-gp and MRP2, thereby providing beneficial information for appropriate use of SP for clinical therapy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Astragali radix ("Huang Qi" in Chinese, HQ) is a well-known traditional Chinese herbal medicine that possesses various biological functions. Astragaloside IV (AS-IV), calycosin (CS), and formononetin (FMNT) are the three main bioactive compounds of HQ that are responsible for its pharmacological activities and therapeutic efficacy., Aim of the Study: This study aims to investigate the effects of HQ, AS-IV, CS, and FMNT on major human drug-metabolizing enzymes (DMEs), including CYP3A4, CYP2B6, CYP2E1, UGT1A, UGT1A6, SULT1A1, and SULT1A3, as well as efflux transporters (ETs), including P-gp, MRP2, BCRP, MRP1, and MRP3, by using HepG2 cell line. Results would provide beneficial information for the proper clinical application of HQ., Materials and Methods: HepG2 cells were treated with HQ, AS-IV, CS, and FMNT for 96h. Cell viability was examined by MTT assay. The protein and mRNA levels of DMEs and ETs were measured using Western blot and real-time PCR, respectively., Results: Compared with the control group, HQ considerably increased the expression levels of CYP3A4, CYP2B6, CYP2E1, UGT1A, P-gp, MRP2, BCRP, and MRP3 in a dose-dependent manner. Inversely, HQ significantly decreased the protein levels of UGT1A6, SULT1A1, and MRP1. Exposure to AS-IV induced the protein levels of UGT1A, P-gp, MRP1, and MRP3, but produced inhibitory effects on CYP3A4, CYP2B6, and BCRP. The expression levels of CYP3A4, UGT1A, SULT1A1, P-gp, MRP2, and MRP3 were remarkably increased in the CS-treated cells, whereas the protein levels of SULT1A3 and BCRP were decreased. FMNT treatment induced the protein levels towards CYP3A4, CYP2B6, UGT1A, P-gp, MRP1, MRP2, and MRP3, but inhibited the expression of CYP2E1, SULT1A1, and SULT1A3., Conclusions: HQ and its main bioactive compounds, including AS-IV, CS, and FMNT significantly regulated the expression of the major DMEs and ETs. HQ produced stronger regulations (induction or inhibition) on DMEs and ETs than AS-IV, CS, or FMNT alone. The results indicate that potential drug-drug interactions might exist when the tested drugs, specifically HQ, are co-administered with other substrate drugs that are metabolized or transported via the studied DMEs or ETs. This study provides beneficial information for appropriate use of HQ for clinical therapy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)