Schisandra chinensis regulates drug metabolizing enzymes and drug transporters via activation of Nrf2-mediated signaling pathway

Abstract

Drug metabolizing enzymes (DMEs) and drug transporters are regulated via epigenetic, transcriptional, posttranscriptional, and translational and posttranslational modifications. Phase I and II DMEs and drug transporters play an important role in the disposition and detoxification of a large number of endogenous and exogenous compounds. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a critical regulator of a variety of important cytoprotective genes that are involved in disposition and detoxification of xenobiotics. Schisandra chinensis (SC) is a commonly used traditional Chinese herbal medicine that has been primarily used to protect the liver because of its potent antioxidative and anti-inflammatory activities. SC can modulate some DMEs and drug transporters, but the underlying mechanisms are unclear. In this study, we aimed to explore the role of Nrf2 in the regulatory effect of SC extract (SCE) on selected DMEs and drug transporters in human hepatocellular liver carcinoma cell line (HepG2) cells. The results showed that SCE, schisandrin A, and schisandrin B significantly increased the expression of NAD(P)H: Nicotinamide Adenine Dinucleotide Phosphate-oxidase or:quinone oxidoreductase 1, heme oxygenase-1, glutamate–cysteine ligase, and glutathione S-transferase A4 at both transcriptional and posttranscriptional levels. Incubation of HepG2 cells with SCE resulted in a significant increase in the intracellular level of glutathione and total glutathione S-transferase content. SCE significantly elevated the messenger ribonucleic acid and protein levels of P-glycoprotein and multidrug resistance-associated protein 2 and 4, whereas the expression of organic anion transporting peptide 1A2 and 1B1 was significantly downregulated by SCE. Knockdown of Nrf2 by small interfering ribonucleic acid attenuated the regulatory effect of SCE on these DMEs and drug transporters. SCE significantly upregulated Nrf2 and promoted the translocation of Nrf2 from cytoplasm to the nuclei. Additionally, SCE significantly suppressed the expression of cytosolic Kelch-like ECH-associated protein 1 (the repressor of Nrf2) and remarkably increased Nrf2 stability in HepG2 cells. Taken together, our findings suggest that the hepatoprotective effects of SCE may be partially ascribed to the modulation of DMEs and drug transporters via Nrf2-mediated signaling pathway. SCE may alter the pharmacokinetics of other coadministered drugs that are substrates of these DMEs and transporters and thus cause unfavorable herb–drug interactions.

Schisandra chinensis Stem Ameliorates 3-Nitropropionic Acid-Induced Striatal Toxicity via Activation of the Nrf2 Pathway and Inhibition of the MAPKs and NF-κB Pathways

“…Schisandra chinensis and its components have antioxidant and neuroprotective effects through Nrf2 transcriptional activation (Chen et al, 2008 ; He et al, 2014 ; Giridharan et al, 2015 ). Therefore, we investigated the effect of SSCE on the Nrf2 pathway.…”

“…The main ingredients of SSC, which include gomisin A/J/N and schisandrin (schizandrin) A/B/C, were also separated from the FSC (Lu and Chen, 2009 ; Zheng et al, 2014 ; Zhu et al, 2015 ). FSC extract and its constituents have beneficial effects in the treatment of various diseases including neurological diseases, such as cognitive and motor dysfunction (Panossian and Wikman, 2008 ), through anti-apoptotic (total extract and schisandrin B), anti-oxidative (total extract, schisandrin A, and schisandrin B), synaptic transmission (deoxyschizandrin), and anti-neuroinflammatory activities (schisandrin B and gomisin A) (Chen et al, 2008 ; Fu et al, 2008 ; He et al, 2014 ; Wang, X. et al, 2014 ; Giridharan et al, 2015 ; Zhang et al, 2015 ), which confirms the effects of FSC that have been reported by practitioners of traditional medicine (Huh, 1613 ). SSC also includes anwuweizic acid, daucosterol, (+)-deoxyschizandrin, (–)-dihydroguaiaretic acid, gomisin N, henrischinin A-C, schicagenin A-C, schinchinenin A-H, schinchinenlactone A-C, γ-schizandrin, β-sitosterol, tetradecanoic acid, and wuweizisu C (Shi et al, 2011 ; Song et al, 2013 ; Zheng et al, 2014 ).…”

Influence of Different Plant Extracts on CYP-Mediated Skatole and Indole Degradation in Pigs

“…The fruits, leaves, and stems of Schisandra chinensis contain dibenzo[a,c]cyclooctadiene lignans and are thus suggested to have bioactive properties [ 17 ]. An in vitro study examining the hepatic effects of Schisandra chinensis confirmed its role in activating Nrf-2 on HepG2 cell lines [ 18 ]. Nrf-2 activation is known to mediate the activation of target genes involved in phase I and phase II liver metabolism [ 19 ].…”

Ginsenoside Rb1 and Rd Remarkably Inhibited the Hepatic Uptake of Ophiopogonin D in Shenmai Injection Mediated by OATPs/oatps

“…These are exclusively expressed in the basolateral membrane of the liver and are responsible for the uptake of a wide variety of endogenous and exogenous substrates, such as antidiabetics, antineoplastics, HMG-CoA reductase inhibitors and so on ( Klatt et al, 2013 ; Van De Steeg et al, 2013 ; Kunze et al, 2014 ; Marada et al, 2015 ). Furthermore, several studies have shown that many herbal ingredients may impact the transportation of substrates mediated by OATP1B1/1B3 ( Mandery et al, 2012 ; Zhang et al, 2013 ; He et al, 2015 ; Sheng et al, 2015 ). The interactions among these herbal ingredients based on OATPs might be one of the important compatibility mechanisms of TCM.…”