Radix Paeoniae Alba attenuates Radix Bupleuri-induced hepatotoxicity by modulating gut microbiota to alleviate the inhibition of saikosaponins on glutathione synthetase

• Published in: Journal of pharmaceutical analysis Vol. 13; no. 6; pp. 640 - 659
• Main Authors: Chen, Congcong, Gong, Wenxia, Tian, Junshen, Gao, Xiaoxia, Qin, Xuemei, Du, Guanhua, Zhou, Yuzhi
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.06.2023; Xi'an Jiaotong University, Journal of Pharmaceutical Analysis; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province,Shanxi University,Taiyuan,030006,China%Modern Research Center for Traditional Chinese Medicine,The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education,Shanxi University,Taiyuan,030006,China; Institute of Materia Medica,Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing 100050,China; Modern Research Center for Traditional Chinese Medicine,The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education,Shanxi University,Taiyuan,030006,China; Xi'an Jiaotong University; Elsevier
• Subjects: Apoptosis; Bioavailability; Chinese medicine; Combination mechanisms; Deglycosylation; Digestive system; Drug dosages; Gastrointestinal tract; Glutathione; Gut microbiota; Hepatotoxicity; Herbal medicine; Inflammation; Intestinal microflora; Kinases; Liver; Metabolism; Microbiota; NF-κB protein; Original; Oxidative stress; Proteins; Radix Bupleuri; Radix Paeoniae Alba; Saikosaponins; Saponins; Tumor necrosis factor-TNF; Beijing China; United States > US; China; Gut microbiota; Radix Bupleuri; Combination mechanisms; Saikosaponins; Hepatotoxicity; Radix Paeoniae Alba
• ISSN: 2095-1779; 2214-0883
• DOI: 10.1016/j.jpha.2023.04.016

Radix Bupleuri (RB) is commonly used to treat depression, but it can also lead to hepatotoxicity after long-term use. In many anti-depression prescriptions, RB is often used in combination with Radix Paeoniae Alba (RPA) as an herb pair. However, whether RPA can alleviate RB-induced hepatotoxicity remain unclear. In this work, the results confirmed that RB had a dose-dependent antidepressant effect, but the optimal antidepressant dose caused hepatotoxicity. Notably, RPA effectively reversed RB-induced hepatotoxicity. Afterward, the mechanism of RB-induced hepatotoxicity was confirmed. The results showed that saikosaponin A and saikosaponin D could inhibit GSH synthase (GSS) activity in the liver, and further cause liver injury through oxidative stress and nuclear factor kappa B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway. Furthermore, the mechanisms by which RPA attenuates RB-induced hepatotoxicity were investigated. The results demonstrated that RPA increased the abundance of intestinal bacteria with glycosidase activity, thereby promoting the conversion of saikosaponins to saikogenins in vivo. Different from saikosaponin A and saikosaponin D, which are directly combined with GSS as an inhibitor, their deglycosylation conversion products saikogenin F and saikogenin G exhibited no GSS binding activity. Based on this, RPA can alleviate the inhibitory effect of saikosaponins on GSS activity to reshape the liver redox balance and further reverse the RB-induced liver inflammatory response by the NF-κB/NLRP3 pathway. In conclusion, the present study suggests that promoting the conversion of saikosaponins by modulating gut microbiota to attenuate the inhibition of GSS is the potential mechanism by which RPA prevents RB-induced hepatotoxicity. Radix Paeoniae Alba attenuates Radix Bupleuri-induced hepatotoxicity via the gut-liver axis metabolic pathway. “San”: Radix Bupleuri is the herb of “Xin San”; “Shou”: Radix Paeoniae Alba is the herb of “Suan Shou”. [Display omitted] •RPA effectively reversed RB-induced hepatotoxicity in depression model rats.•RPA attenuates RB-induced hepatotoxicity via the gut-liver axis metabolic pathway.•RPA can promote the conversion of saikosaponins by modulating gut microbiota.