Liver disorders, such as hepatitis, fatty liver disease, liver cancer, and cirrhosis; liver toxicity as a result of drugs and alcohol; mushroom poisoning.
Mechanism of Action
Flavonoids in Bupleurum are credited with hepatoprotective actions and include rutin and narcissin. Narcissin is the dominant flavonoid in Bupleurum flavum, whereas other species may be higher in rutin. Narcissin displays an antioxidant action in liver cells that is similar or stronger than that of silymarin, and it is capable of reducing elevated lactate dehydrogenase and malondialdehyde.1
Bupleurum also contains saikosaponins, a group of terpenoid compounds credited with immune-modulating effects. Bupleurum saikosaponins A, B, C, and D may inhibit hepatitis viruses in the early phases of the viral life cycle by inhibiting entry into cells without significant cytotoxicity to hepatocytes.2 Saikosaponin B has particularly been shown to inhibit viral particles and prevent viral attachment and cellular entry in cultured human hepatocytes.2
Bupleurum saikosaponins may have cytoprotective effects by alleviating stress on the endoplasmic reticulum, stabilizing and restoring mitochondrial function, inducing cell recovery pathways, and inhibiting apoptosis.3 Saikosaponins have been shown to prevent excessive proliferation of hepatic stellate cells, promote wound healing, and induce apoptosis. These positive effects are associated with decreases in the expressions of extracellular matrix, platelet-derived growth factor, hepatic collagen deposition, and connective tissue growth factor.4,5,6 These mechanisms are believed to contribute to antifibrotic effects in acute and chronic liver inflammation.
Additional mechanisms of hepatoprotection include cyclooxygenase (COX) inhibition. COX expression has been found to be increased in animal models of induced liver cancer. Saikosaponin D is a COX inhibitor that contributes to inhibiting liver fibrosis in active disease, and it may also provide chemoprevention in chronic inflammatory diseases of the liver.7 The proinflammatory cytokine tumor necrosis factor-α was also significantly reduced by Bupleurum chinense.8
Animal research suggests that Bupleurum can protect the liver from carbon tetrachloride,6 tert-butyl hydroperoxide,1 and acetaminophen9 and increase the efficacy of 5 fluorouracil against liver cancer.10 Bupleurum may reduce fibrotic changes in the liver,5,6 improve obstructive jaundice,11 and decrease hepatocarcinogenesis in chronic liver inflammation.7 Bupleurum exerts a hepatoprotective effect in galactosamine-induced liver inflammation in mice, significantly reducing aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, and lactate dehydrogenase activities and increasing glutathione and superoxide dismutase at a dose of 400 mg/kg/day.
Safety in Pregnancy and Breastfeeding
Because of hepatoxicity concerns (when taking Bupleurum at high doses), Bupleurum is contraindicated in pregnancy and lactation.
Despite its hepatoprotective effects, Bupleurum can also exert hepatotoxic effects at a very high dose and duration, and even induce fatal hepatotoxicity at doses from 50 to 125 g/kg in 1–2 weeks’ time in rats.12 The toxic effects included fatty degeneration at moderate doses, progressing to necrotic lesions at the highest dosages. Alcohol extractions of Bupleurum have shown greater hepatotoxicity than water extracts.13
Possible liver injury in humans has been reported14 from B. chinense with anecdotal reports of inducing fibrosis, even though research has shown the plant to prevent liver fibrosis. There were reports of renal and liver injury associated with the use of an injectable Bupluerum preparation in Japan in the 1980s that combined the herb with interferon and other compounds. The adverse effects were proposed to be the result of hypersensitivity reactions and included two cases of hypokalemia and renal failure associated with the use of an intravenous preparation, one of which was fatal via hypersensitivity shock.15
One epidemiological study surveyed >600,000 patients hospitalized for hepatitis B infection and investigated any association between the use of Bupleurum and the risk of being hospitalized for liver injury. The researchers reported that the use of Bupleurum containing traditional Chinese prescriptions of more than 19 g16 was associated with an increased risk of being hospitalized for liver disease.
A rat toxicity study investigated three dosages of B. chinense, 50, 150, and 300 mg/kg, on hepatic function, renal function, and the metabolism of lipids and carbohydrates. They found a dose-dependent hepatic tissue damage associated with increased liver enzymes and visible hepatic tissue damage.17 Bupleurum at a dose of 1 mg/kg for 4 or 8 weeks was also shown to increase liver enzymes (AST and ALT), immunoglobulins, and antinuclear antibody in the blood and to elevate interferon-γ, interleukin-10, and transforming growth factor-β1 levels in liver tissues, along with necroinflammatory changes seen with histological sampling.18 In summary, the above-mentioned data suggest caution and close monitoring in patients with hepatitis B who concomitantly use interferon and Bupleurum.
Saikosaponins may be altered when B. chinense root is baked in vinegar, and their absorption may also be altered. It is possible that this extraction method may increase the liver toxicity risk of Bupleurum species.
Typical dosages are 100–500 mg QD to BID, but Bupleurum species are often combined at 50–200 mg
in multiherb formula taken QD to BID.
The root of various Bupleurum species (B. chinense, B. falcatum) are well-known as medicinal plants
in China and are listed in the oldest Chinese materia medica documents, the Shennong’s Herbal. Bupleurum was described as having the action of “soothing liver and relieving constraint,” useful for improving both frank liver symptoms and improving emotional instability such as depression, anxiety, and phobia. Bupleurum is used in folk medicine as an anti-inflammatory and pain remedy.
Pharmacogn Mag. 2015;11(41):14–23. Flavonoid profiles of three Bupleurum species and in vitro hepatoprotective of activity Bupleurum flavum Forsk. Gevrenova R, Kondeva-Burdina M, Denkov N, Zheleva-Dimitrova D.
2 J Hepatol. 2015;62(3):541–8. Saikosaponin b2 is a naturally occurring terpenoid that efficiently inhibits hepatitis C virus entry. Lin LT, Chung CY, Hsu WC, Chang SP, Hung TC, Shields J, Russell RS, Lin CC, Li CF, Yen MH, Tyrrell DL, Lin CC, Richardson CD.
3 J Ethnopharmacol. 2013;148(3):794–803. Neuroprotective effects of total saikosaponins of Bupleurum yinchowense on corticosterone-induced apoptosis in PC12 cells. Li ZY, Guo Z, Liu YM, Liu XM, Chang Q, Liao YH,
4 J Med Food. 2013;16(9):793–800. Saikosaponin a and saikosaponin d inhibit proliferation and migratory activity of rat HSC-T6 cells. Chen MF, Huang CC, Liu PS, Chen CH, Shiu LY.
5 Phytomedicine. 2013;20(14):1330–5. Saikosaponin A of Bupleurum chinense (Chaihu) elevates bone morphogenetic protein 4 (BMP-4) during hepatic stellate cell activation. Wang X, Wang Q, Burczynski FJ, Kong W, Gong Y.
6 Am J Chin Med. 2010;38(1):99–111. Curcumin and saikosaponin a inhibit chemical-induced liver inflammation and fibrosis in rats. Wu SJ, Tam KW, Tsai YH, Chang CC, Chao JC.
7 Mol Med Rep. 2012;5(3):637–44. Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: involvement of CCAAT/enhancer binding protein β and cyclooxygenase-2. Lu XL, He SX, Ren MD, Wang YL, Zhang YX, Liu EQ.
8 Carbohydr Polym. 2012;89(2):448–52. Antioxidant activity and hepatoprotective effect of a polysaccharide from Bei Chaihu (Bupleurum chinense DC). Zhao W, Li JJ, Yue SQ, Zhang LY, Dou KF.
9 Chem Biol Interact. 2014;223C:80–6. Saikosaponin d protects against acetaminophen-induced hepatotoxicity by inhibiting NF-κB and STAT3 signaling. Liu A, Tanaka N, Sun L, Guo B, Kim JH, Krausz KW, Fang Z, Jiang C, Yang J, Gonzalez FJ.
10 Basic Clin Pharmacol Toxicol. 2008;103(4):305–13. Effect of Bupleuri Radix extracts on the toxicity of 5-fluorouracil in HepG2 hepatoma cells and normal human lymphocytes. Kang SJ, Lee YJ, Kim BM, Kim YJ, Woo HD, Jeon HK, Chung HW.
11 Int J Sports Med. 2012;33(7):572–9. Intervention of TLR4 signal pathway cytokines in severe liver injury with obstructive jaundice in rats. Lin L, Cai WM, Qin CJ, Miao LC, Yun LT, Hua Y, Weilin L.
12 Zhongguo Zhong Yao Za Zhi. 2010;35(24):3344–7. “Dose-time-toxicity” relationship study on hepatotoxicity caused by multiple dose of total Bupleurum saponin crude extracts to rats. Huang W, Sun R, Zhang Z.
13 Zhongguo Zhong Yao Za Zhi. 2009;34(18):2364–8. Comparative research of different Bupleurum chinense composition to influence of hepatotoxicity of rats and oxidative damage mechanism. Lv L, Huang W, Yu X, Ren H, Sun R.
14 Dig Liver Dis. 2014;46(3):264–9. Herbal hepatotoxicity: analysis of cases with initially reported positive re-exposure tests. Teschke R, Genthner A, Wolff A, Frenzel C, Schulze J, Eickhoff A.
15 Zhongguo Zhong Yao Za Zhi. 2014;39(15):2983–8. “Re-evaluation upon suspected event” is an approach for post-marketing clinical study: lessons from adverse drug events related to Bupleuri Radix preparations. Wu SX, Sun HF, Yang XH, Long HZ, Ye ZG, Ji SL, Zhang L.
16 PLoS One. 2011;6(1):e16064. Risk of liver injury associated with Chinese herbal products containing radix bupleuri in 639,779 patients with hepatitis B virus infection. Lee CH, Wang JD, Chen PC.
17 Zhongguo Zhong Yao Za Zhi. 2010;35(17):2338–41. “Dose-toxicity” relationship study on rat’s chronic hepatoxicity of refined products of saikosaponin by alcohol elution. Sun R, Huang W.
18 Liver Int. 2014;34(4):583–93. Herb-induced autoimmune-like hepatitis in C57BL/6J mice. Wang JY, Lee CY, Pan PJ, Chang WC, Chiu JH, Chen WS, Shyr YM.