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

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.

[Effect of Chinese herbal medicine with Supplement Qi and Activating Blood Circulation on tubular reabsorption function of diabetic nephropathy rats].

OBJECTIVE: To investigate the effect of Chinese herbal medicine with Supplement Qi and Activating Blood Circulation (huangqi and danshen) on urinary protein, kidney function and tubular reabsorption of diabetic nephropathy rats. METHODS: SD rats were randomly divided into a nondiabetic control group (normal group) and three groups in which diabetes were induced by a single intraperitoneal injection of freshly prepared streptozotocin( STZ,55 mg/kg body weight). Then the diabetes rats were randomly assigned to three groups: diabetic model group, Supplement Qi and Activating Blood Circulation traditional Chinese medicine group (huangqi and danshen group) and Gliquidone group (as a reference hypoglycemic drug). Each group was treated with corresponding drugs for 6 weeks. At the end of the study, the rats from each group were injected with FITC-labeled BSA through tail vein. The 24 h urinary protein excretion were measured and blood was collected for measuring plasma glucose levels, serum creatinine (Cr), blood urea nitrogen (BUN), triglyceride (TG) and total cholesterol (T-CHO). Renal tissue was used to measure the level of LPO,SOD,GSH-Px and AGEs and Paraffin-embedded sections were stained with HE, PAS and immunohistochemistry. RESULTS: The plasma glucose, the 24 h urinary protein excretion, the levels of serum Cr, BUN, TG and T-CHO in STZ-induced diabetic rats were higher than those of nondiabetic rats. Diabetic rats showed significantly increase in LPO and AGEs (P < 0.01) and decrease in antioxidant enzyme activity (both GSH-Px and SOD) (P < 0.05) as compared with non-diabetic control rats. Treatment with the Supplement Qi and Activating Blood Circulation traditional Chinese medicine for 6 weeks in diabetic rats significantly reduced the 24 h urinary protein excretion compared with model control (P < 0.01), and markedly decreased the levels of serum Cr,BUN,TG and T-CHO as compared with those of diabetic rat (P < 0.05). The levels of LPO and AGEs were decreased and the activity of GSH-Px was increased by Supplement Qi and Activating Blood Circulation treatment. The kidney proximal tubule lesions were improved and the reabsorption of FITC-BSA in tubular was increased in diabetic rats treated by huangqi and danshen, and the expression of megalin in proximal tubular was enhanced as compared with diabetic rats. CONCLUSION: Diabetic nephropathy rats treated with traditional Chinese medicine therapeutic principles "Supplement Qi and Activating Blood Circulation" can reduce the 24 h urinary protein excretion and improve the function of tubular reabsorption. These protect effects may be in correlation with enhancement the renal tissue activity of antioxidant and up-regulation the expression of megalin in renal tubular epithelial cells in diabetic rats.