Sickle-leaf Hare's Ear (Bupleurum falcatum L.)
1. Identity and Botanical Description
Bupleurum falcatum, the sickle-leaved hare's ear, sickle hare's ear, or sickle-leaf hare's ear, is a species of flowering plant in the family Apiaceae. It is also known in some literature as Chinese thoroughwax. It is found in Europe and the Caucasus. In East Asia, the scientific name Bupleurum falcatum is often misapplied to another species, Bupleurum stenophyllum.
The scientific name holds clues to the plant's characteristics: the genus name "Bupleurum" comes from the Greek "bupleuros," which means "to have a good root," reflecting its strong root systems. The species epithet falcatum refers to the sickle-shaped (falcate) leaves that characterize the plant. It is primarily native to the cooler temperate zones of Europe and parts of Asia, where it is characterized by its unique leaf shape that resembles a sickle, thriving in grasslands and open woodlands.
Three subspecies are recognized: Bupleurum falcatum subsp. corsicum (Corsica), subsp. dilatatum (Slovakia, Hungary, and Romania), and subsp. falcatum (France to the Caucasus and eastern European Russia).
The plant typically reaches a height of 30 to 90 cm. It features a robust, upright stem with alternate, lanceolate leaves. The leaves are bright green with a glossy appearance. The plant produces small, yellow-green flowers arranged in umbels, characteristic of the Apiaceae family. The flowering period usually occurs in late summer to early fall, after which it produces small, dry fruits known as schizocarps, which split into two parts upon maturity.
The long cone- or column-shaped, single or branched root is 10 to 20 cm in length and 0.5 to 1.5 cm in diameter; the root is light brown to brown, may be wrinkled, and is easily broken.
Nomenclature and Taxonomic Notes
The plant is known by several common and technical names in medicinal literature, including Beichaihu, Bupleuri Radix, Bupleurum root, Chai-hu, Chaihu, Hare's ear root, Radix Bupleuri, and Saiko (Japanese). Synonyms of B. falcatum in some taxonomic treatments include Bupleurum chinense DC. and Bupleurum scorzonerifolium Willd. The root of B. chinense DC. is considered the genuine Chaihu, but other species have been included in the Pharmacopoeia of the People's Republic of China since 1963, including bei Chaihu and nan Chaihu (referring to northern and southern thorowax root).
Pharmacopoeial Status
Bupleurum falcatum L. is officially listed in the Japanese Pharmacopoeia, as well as WHO monographs on selected medicinal plants in China and Korea. Bupleurum species are officially listed in the Chinese and Japanese Pharmacopoeias in addition to the WHO monographs of the commonly used medicinal plants of China and Korea. However, none of the Bupleurum plants were selected by the German Commission E, the British Pharmacopoeia 2009, or the British National Formulary 57.
In Japan, in the Japanese Pharmacopoeia (16th edition), the official botanical origin of Bupleuri Radix (saiko in Japanese) is the roots of B. falcatum L. In Japan and Taiwan, B. falcatum L. is believed to have therapeutic effects against chronic hepatitis and autoimmune diseases.
Common Forms and Preparations
Bupleuri Radix is typically used in the form of "Xiaochaihu decoction"/extract or "Chaihu Shugan powder"/dried root powder, and it was an indispensably important component in many classic traditional Chinese medicine preparations. Generally, 500–2,000 mg bupleurum dry root are taken three times daily in capsules. Traditionally, and in some clinical studies, bupleurum was prepared as a tea in which the root is decocted or cooked for hours before use; some formulations use 1–4 grams per cup of water, three times daily.
Several Bupleurum species have been used either alone or in combination with other ingredients for the treatment of the common cold, inflammatory disorders, hepatitis, cancer, and fever in the form of over-the-counter herbal teas or in different pharmaceutical preparations. Bupleurum falcatum root extract, derived from the rhizomes of the plant, is also used in cosmetic and personal care formulations.
2. Traditional and Historical Use
Traditional Chinese Medicine
B. falcatum has been used in Chinese medicine for over 2,000 years as a "liver tonic." It is commonly prescribed by both Chinese and Japanese traditional medicine doctors for inflammatory and infectious diseases.
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 falcatum root (chai hu) as a medicinal herb first appeared in the Divine Husbandman's Classic of the Materia Medica (Shen Nong Ben Cao Jing), written in the Eastern Han Dynasty (25–220 CE). The Treatise on Shanghan and Other Diseases (Shang Han Za Bing Lun) by the physician Zhang Zhong-Jing also appeared at the end of the Han Dynasty, 220 CE. During the Jin Dynasty (3rd century), Wang Shu-he gathered the book together from various sources and published it in two volumes; the formulas in the Discussion of Cold-Induced Disorders included the formula Minor Bupleurum (Xiao Chai Hu Tang).
In TCM theory, Bupleurum falcatum is a bitter, acrid, cooling herb entering the channels of the Gall Bladder, Liver, Pericardium, and Triple Burner. It has a lifting, dispersing, and draining action useful in releasing pathogens from the exterior, draining heat, and regulating Qi. This makes it particularly effective in treating Shao Yang syndrome, one of the six stages of disease progression explained in the Shang Han Lun.
Bupleurum has also traditionally been used to promote perspiration and treat fever associated with influenza, the common cold, malaria, and pneumonia; flu; distending pain in the chest; and menstrual disorders.
Traditional Korean and Japanese Medicine
The root of Bupleurum falcatum L. has been used in traditional Korean and Chinese medicines for over 2,000 years to treat infections, fever, and chronic liver diseases. Traditionally, its dried roots ("Shiho" in Korean), the part used for medicinal purposes, have been widely used for treating the common cold, fever, hepatitis, inflammation, and also the symptoms of menopausal syndrome, such as hot flashes and depressive mood change.
In Kampo medicine (traditional Japanese medicine), Shosaikoto (Xiao-Chai-Hu-Tang) is clinically used for the treatment of various feverish diseases such as the common cold, pleuritis, and pneumonia, hepatic function diseases, and chronic enterogastric diseases. These Kampo medicines are commonly used in medical treatment covered by health insurance in Japan since 1976.
Traditional Use in Other Cultures
The genus Bupleurum, comprising approximately 248 accepted species, is widely distributed and used in China, Japan, India, Central Asia, North Africa, and some European countries as traditional herbal medicine. Bupleurum is also used in folk medicine as an anti-inflammatory and pain remedy.
Bupleurum is an important herb used in traditional Chinese and Japanese medicine. It is frequently prescribed in combination with other herbs to treat colds, fever, digestive disorders, chronic liver diseases, and depression symptoms. Herbal formulas such as Xiao Chai Hu Tang (Sho-saiko-to) and Xiao Yao San contain bupleurum as a major ingredient.
3. Key Constituents and Active Compounds
Overview of Phytochemistry
The main chemical constituents identified in B. falcatum include saponins, coumarins, polysaccharides, fatty acids, flavonoids, lignans, polyacetylenes, and steroids. Among these, saikosaponins constitute 1.5–3.5% and are the core active components. The polysaccharide content ranges from 2% to 5%, with neutral polysaccharides making up approximately 70%. The flavonoid content is between 0.2% and 1.5%, volatile oils constitute 0.1–0.3%, coumarins range from 0.05% to 0.2%, and polyacetylenes are present at 0.01–0.1%.
Saikosaponins (Triterpene Saponins)
Bupleurum contains triterpene saponins or saikosides, also known as saikosaponins. Levels of saikosaponins vary widely between species (i.e., B. falcatum 2% to 8% and B. chinense 1.7%) and between wild and cultivated species. Levels also depend upon growing conditions.
Saikosaponins generally constitute the main class of secondary metabolites in the genus Bupleurum, accounting for up to 7% of the total dry weight of the roots. In recent years, more than 120 glycosylated oleanane-type and ursane-type saikosaponins have been isolated from Bupleurum species.
The aglycones of these saikosaponins are closely related oxygenated pentacyclic triterpenoidal structures that can be distinguished only by the positions and numbers of the double bonds in rings C and D and oxygenation patterns in positions 16, 23, 28, and 30. These saponins generally bear one (monodesmosidic) or, less often, two (bidesmosidic) carbohydrate chains that are directly attached to the hydroxyl groups in position 3 for monodesmosidic saponins. The carbohydrate chains are composed mainly of fucose, rhamnose, xylose, galactose, and glucose moieties.
Three new saponins and nine known saponins have been isolated from the dried roots of Bupleurum falcatum. New compounds named 4''-O-acetylsaikosaponin d and hydroxysaikosaponins a and c have been characterized. In aqueous acidic conditions, saikosaponins a and d were converted into saikosaponins b1 and b2, as well as hydroxysaikosaponins a and d, respectively.
The principal saikosaponins studied from B. falcatum include saikosaponin A (SSA), saikosaponin B (SSB), saikosaponin C (SSC), and saikosaponin D (SSD). Several major triterpenoid saponins have been identified in B. falcatum extract, including saikosaponin A (SSA) and saikosaponin D (SSD). These active components are reported to impart immunomodulatory, anti-inflammatory, antibacterial, antiviral, and anticancer effects. Saikosaponin A (SSA), a triterpene saponin derived from Bupleurum falcatum, has immunoregulatory, neuromodulatory, antiviral, anticancer, anti-convulsant, anti-inflammatory, and anti-proliferative effects.
Polysaccharides (Bupleurans)
Rare monosaccharides, like ribitol, xylose, and arabinose, and pectic polysaccharides, like bupleuran 2IIb and bupleuran 2IIc, have been isolated from B. falcatum and many other species; these compounds exert anti-ulcer, anti-inflammatory, anti-infective, and immunomodulatory effects in autoimmune diseases.
Flavonoids
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.
Other Constituents
Free organic and fatty acids, like pinellic acid, angelic acid, petroselic acid, and lignoceric acid, have also been identified in many species of Bupleurum. Anti-aggregating effects on platelets by the lactone bupleurumin (extracted from the aerial parts of B. falcatum) have been demonstrated in vitro.
4. Mechanisms of Action
Anti-inflammatory Mechanisms
A wide range of Bupleurum preparations has been shown to affect artificially induced acute and chronic inflammation in animal models and, in addition, exert a marked in-vitro activity on inflammatory mediators resulting from the inhibition of either lipoxygenases or cyclooxygenase.
Treatment with B. falcatum ethanol extract (BFE) or saikosaponins dose-dependently attenuated LPS-induced production of NO, iNOS mRNA, and ROS by 30–50%. They reduced LPS-mediated increases in the mRNA levels of IL-6, IL-1β, and TNF-α by approximately 30–70% without affecting cell viability, and decreased LPS-mediated NF-κB activity via reducing p65/RELA mRNA, transcriptional activity, and nuclear localization of NF-κB.
Saikosaponin D (compound 3) isolated from B. falcatum roots inhibited the interaction of selectins (E, L, and P) and THP-1 cells with IC50 values of 1.8, 3.0, and 4.3 µM, respectively. The aglycone structure also showed moderate inhibitory activity on L-selectin-mediated cell adhesion, suggesting saikosaponin D as a candidate for therapeutic strategies to treat inflammation.
Hepatoprotective Mechanisms
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. Saikosaponin B has particularly been shown to inhibit viral particles and prevent viral attachment and cellular entry in cultured human hepatocytes. 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. Saikosaponins have been shown to prevent excessive proliferation of hepatic stellate cells, promote wound healing, and induce apoptosis.
Immunomodulatory Mechanisms
The pectic polysaccharide bupleuran 2IIc from the roots of Bupleurum falcatum L. acts on interleukin-6 (IL-6) production of murine B cells and B cell lines. Bupleuran 2IIc enhanced IgM secretion from highly purified murine normal B cells. When normal B cells were cultured with bupleuran 2IIc in the presence of anti-IL-6 neutralizing antibody, the enhanced IgM secretion was reduced. When B cells were stimulated with bupleuran 2IIc, their IL-6 secretion and the transcription of IL-6 mRNA were enhanced.
Bupleuran 2IIc was also shown to enhance G-CSF secretion, including in primary cultured colonic epithelial cells. Digestion studies identified that the "ramified" region of bupleuran 2IIc is the active site for this G-CSF secretion–enhancing activity, and the arabinan moiety plays an important role in expression of the activity.
Antidepressant/Neuromodulatory Mechanisms
Bupleurum falcatum has been found to possess antidepressant properties, mediated through the serotonergic and noradrenergic systems, although the precise mechanism remains to be found. In the perimenopausal depression model of female rats induced by CUMS, saikosaponin A can improve the behavioral performance of these rats and reduce CRH mRNA, CRH protein, and serum CORT levels in the rat hypothalamus, while inhibiting the overexpression of hippocampal proinflammatory cytokines.
Antiviral Mechanisms
The antiviral effects of saikosaponin D isolated from the roots of B. falcatum against herpes simplex, poliovirus, and measles were investigated. Saikosaponin D at a 5 mM concentration directly inactivated both measles virus and herpes simplex virus, while a 500 mM concentration resulted in complete loss of viral infectivity. However, saikosaponin D was ineffective against the replication of measles virus, herpes virus, and poliovirus.
Metabolic Actions
Among the saikosaponins isolated from Bupleurum falcatum L., saikosaponins a and d, but not c, had metabolic actions as well as anti-inflammatory action. These metabolic actions and anti-inflammatory action may confirm the clinical application of Bupleurum falcatum L., which has been widely used in the prescriptions of oriental medicine, and may suggest possible mechanisms for the actions of its active principles.
5. Scientific Evidence by Area of Use
5.1 Liver and Hepatic Function
Preclinical studies suggest that bupleurum has antiviral, hepatoprotective, anti-inflammatory, immune-modulating, antiproliferative, and chemopreventive properties.
In animal models, 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.
In human and clinical studies, evidence comes primarily from the multi-herb formula Sho-saiko-to (Xiao Chai Hu Tang), in which B. falcatum is a principal component. Human trials, with only one being double-blind, have shown that the bupleurum-containing formula sho-saiko-to may help reduce symptoms and blood liver enzyme levels in children and adults with chronic active viral hepatitis. Most of these studies were in people with hepatitis B infection, though one preliminary human trial has also shown a benefit in people with hepatitis C. Sho-saiko-to was also found, in a large, preliminary (but not double-blind) study, to decrease the risk of people with chronic viral hepatitis developing liver cancer.
A Phase II clinical trial at Memorial Sloan Kettering Cancer Center evaluated Sho-saiko-to (SST) in patients with chronic hepatitis C. All patients received treatment with 2.5 grams of SST as granules in packet form by mouth three times a day every day for 52 weeks. Of 24 participants, 5 were responders and 19 were non-responders, with response defined as an improvement of 2 points or greater in paired comparisons of pre- and post-treatment liver biopsy Knodell's histology activity index scores. The overall response rate in this trial was limited, and its small size constrains firm conclusions.
Strength of evidence: The hepatoprotective evidence for B. falcatum itself is largely preclinical (in vitro and animal). The human clinical data available relate to multi-herb formulas containing bupleurum as a component (predominantly Sho-saiko-to), making it impossible to attribute results to bupleurum alone. Although bupleurum is used along with other herbs in traditional formulas to treat many conditions, studies in humans are lacking.
5.2 Anti-inflammatory Effects
Anti-inflammatory action of saikosaponins isolated from the root of Bupleurum falcatum L. were examined in animal studies using female albino rats. Both anti-exudative action (by granuloma pouch method) and anti-granulomatous action (by cotton pellet method) were demonstrated with intramuscular and oral administrations of saikosaponins. Among saikosaponins isolated from Bupleurum falcatum, saikosaponins a and d, not c, were demonstrated to have anti-inflammatory action.
In-vitro and in-vivo studies on Bupleurum extracts or isolated components (mainly saikosaponins) revealed significant anti-inflammatory, anti-ulcer, and immunomodulatory activity. Other demonstrated activities include hepatoprotective, antitussive, antispasmodic, diaphoretic, antioxidant, and antimicrobial effects.
Strength of evidence: Anti-inflammatory activity is well-supported by in vitro and animal data, including mechanistic studies targeting NF-κB and cytokine pathways. No direct human clinical trials using isolated B. falcatum extract for inflammatory conditions have been identified in the peer-reviewed literature.
5.3 Neurological and Antidepressant Effects
Studies in rodents have focused on the impact of Bupleurum falcatum (BF) extract on repeated restraint stress-induced behavioral responses using the forced swimming test (FST) and elevated plus maze (EPM) test, with immunohistochemical examinations of tyrosine hydroxylase (TH) expression in rat brain. Male rats received daily doses of 20, 50, or 100 mg/kg (i.p.) BF extract for 15 days, 30 minutes prior to restraint stress (4 hours/day). Animals pre-treated with BF extract displayed significantly reduced immobility in the FST and increased open-arm exploration in the elevated plus maze.
At doses of 150 and 300 mg/kg body weight (oral), the methanolic BF extract significantly reduced the total duration of immobility in the tail suspension test, while individual differences in locomotor activities between experimental groups were not observed.
BFE also reduced LPS-induced activation of microglia and astrocytes in the hippocampus and substantia nigra of LPS-injected mice. The data suggest that BFE may be effective for reducing neuroinflammation-mediated neurodegeneration through suppressing NF-κB-mediated inflammatory pathways.
Strength of evidence: Evidence for antidepressant and anxiolytic effects is entirely preclinical (animal studies). Most studies on bupleurum have only been performed in the lab, and human data are lacking. These findings are preliminary and require human clinical investigation.
5.4 Immunomodulation
Present interest is focused on the bioactivity of the isolated triterpene saponins acting as immunomodulatory, anti-inflammatory, and antiviral agents, as well as on the observed anti-ulcer activity of the polysaccharides and anti-proliferative activity of different lignans.
Bupleurum is included in a Chinese herbal formula used for treating a blood disorder called thrombocytopenic purpura, and in the Japanese herbal formula Sho-saiko-to, used for treating various chronic liver diseases such as hepatitis. Sho-saiko-to has been evaluated in a Phase II trial at Memorial Sloan Kettering Cancer Center for use in treating hepatitis C.
Strength of evidence: Immunomodulatory effects are robustly supported by in vitro and animal research. Human evidence remains extremely limited and is confined largely to multi-herb formulas.
5.5 Antiviral Activity
Bupleurum saikosaponins B has been shown to inhibit viral particles and prevent viral attachment and cellular entry in cultured human hepatocytes. Antiviral effects against hepatitis viruses, herpes simplex, and human coronavirus have been investigated in cell-based studies.
Strength of evidence: Antiviral activity is supported by in vitro studies only. No controlled human trials evaluating B. falcatum specifically for antiviral outcomes have been identified.
5.6 Bone and Menopausal Effects
In a clinical trial, a decoction including BF as a major ingredient showed overall efficacy for relieving both the vasomotor and psychological symptoms of postmenopausal women with climacteric symptoms. However, this trial used a multi-herb decoction and cannot be attributed to B. falcatum alone.
In animal studies, female Sprague-Dawley rats were ovariectomized (OVX) and subjected to oral BF treatment daily for 8 weeks, with pre-osteoclastic RAW 264.7 cells also employed to evaluate the effects on RANKL-induced osteoclast formation in vitro. A high dose of BF partially prevented ovariectomy-induced bone loss and reduced the levels of tartrate-resistant acid phosphatase (TRAP) in serum and osteoclast numbers in femurs of OVX rats.
Strength of evidence: Preclinical (animal and cell) data. The one clinical trial identified used a multi-herb decoction; no single-agent human trials for bone or menopausal outcomes have been identified.
5.7 Anti-ulcer Effects
The effects of the acidic polysaccharide fraction from the roots of B. falcatum on induced gastric lesions in mice using different routes of administration have been evaluated. A protective effect was observed after administration by all routes using a concentration range of 25–100 mg/kg. The major acidic polysaccharide with anti-ulcer activity was identified as bupleuran 2IIc after a bioassay-guided fractionation of the sugar fraction.
Strength of evidence: Anti-ulcer effects of B. falcatum polysaccharides are supported by animal model data only. No human clinical data have been identified for this indication.
5.8 Anticancer Properties
Some lignans of Bupleurum species may be useful as anti-mitotic agents in the treatment of cancer by their inhibition of microtubule formation due to their high structural similarity to podophyllotoxin. Saikosaponins, a major constituent, enhanced cisplatin cytotoxicity against solid tumors in preclinical studies.
High-quality clinical trials and a deeper understanding of the pharmacological targets involved in the signalling cascades that govern tumour initiation and progression are needed to facilitate the development of innovative saikosaponin-based treatments.
Strength of evidence: Anticancer research is entirely preclinical (in vitro and animal). The evidence is preliminary, and no human clinical trials for cancer treatment with B. falcatum alone have been identified.
6. Body Systems and Health Areas of Association
- Hepatic / Liver system: Historically used and preclinically investigated as a hepatoprotective and liver tonic agent; implicated in anti-fibrotic and anti-hepatocellular carcinoma research.
- Immune system: Saikosaponins and polysaccharides have been studied as immunomodulatory agents affecting B-cell activity, macrophage function, and cytokine signaling.
- Nervous system / CNS: Investigated for antidepressant and anxiolytic effects via serotonergic and noradrenergic systems in animal models; potential neuroprotective effects against neuroinflammation.
- Inflammatory pathways: Inhibition of NF-κB, cyclooxygenase, and lipoxygenase pathways has been documented in preclinical studies.
- Endocrine / HPA axis: Shown to modulate the hypothalamic-pituitary-adrenal axis in stressed rodents; traditional use for menopausal symptoms.
- Gastrointestinal system: Polysaccharides (bupleurans) have demonstrated anti-ulcer effects in animal models.
- Musculoskeletal / Bone: High-dose BF extract has shown partial protection against estrogen deficiency–induced bone loss in animal studies.
- Cardiovascular system: In vitro and in vivo studies have revealed that Bupleuri Radix exhibits anti-inflammatory, antioxidant, anti-obesity, and anticancer properties with emerging but limited preclinical interest in vascular inflammation.
7. Dosage Forms and Dosages Reported in Studies
Generally, 500–2,000 mg bupleurum dry root are taken three times daily in capsules. Traditionally, and in some clinical studies, bupleurum was prepared as a tea in which the root is decocted or cooked for hours before use. Some protocols use 1–4 grams per cup of water, three times daily.
In the Sho-saiko-to Phase II clinical trial at Memorial Sloan Kettering Cancer Center, all patients received treatment with 2.5 grams of SST as granules in packet form by mouth three times a day, every day, for 52 weeks.
In an animal study of antidepressant effects, male rats received daily doses of 20, 50, or 100 mg/kg (i.p.) BF extract for 15 days, 30 minutes prior to restraint stress (4 hours/day).
In another preclinical antidepressant study, at doses of 150 and 300 mg/kg body weight (oral), the methanolic BF extract significantly reduced the total duration of immobility in the tail suspension test.
In the ovariectomized rat bone loss study, female Sprague-Dawley rats were subjected to oral BF treatment daily for 8 weeks. The specific doses in that study are described as "high dose" with partial bone-protective effects observed.
In studies of hepatoprotective effects in animals, bupleurum has been studied at a dose of 400 mg/kg/day in galactosamine-induced liver inflammation models in mice.
In the anti-ulcer polysaccharide research, a protective effect was observed after administration by all routes using a concentration range of 25–100 mg/kg.
Clinical trial data are lacking to support specific dosing recommendations for humans using B. falcatum as a stand-alone preparation.
8. Safety Considerations and Interactions
General Adverse Effects
Mild lassitude, sedation, and drowsiness have been reported. Large doses may increase flatulence and bowel movements. Allergy to injected bupleurum has been reported.
Hepatotoxicity
The main adverse effect associated with bupleurum root is liver damage, particularly with high doses, which indicates that an established maximum tolerated dose is critical for clinical use of bupleurum root extract and purified compounds.
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 in rats. The toxic effects included fatty degeneration at moderate doses, progressing to necrotic lesions at the highest dosages.
Excessive administration of Radix Bupleuri could result in acute hepatitis and acute hepatic necrosis. Long-term improper use of Radix Bupleuri could also negatively affect the liver function, reflected by transaminase lifts, hepatitis, and jaundice.
In the context of the Sho-saiko-to formula, hepatotoxicity attributed to Sho-saiko-to is usually mild to moderate in severity and rapidly reversible with stopping the medication. No case of acute liver failure, chronic hepatitis, or vanishing bile duct syndrome due to Sho-saiko-to or similar herbal mixtures has been described in the literature. Recurrence upon reexposure is frequent and should be avoided.
Patients treated with the Sho-saiko-to formula (TJ-9) have exhibited acute drug-induced liver injury during a latent period of one and a half to three months. Herbs containing more than 19 grams of Radix Bupleuri in HBV-infected patients were observed to increase the risks of liver injury.
Toxicology Data
Crude saikosaponins show low-medium toxicity in mice, with an oral median lethal dose of 4.7 g/kg and an intramuscular median lethal dose of 112 mg/kg. Methanolic extracts of B. falcatum have not shown mutagenic effects in most modified Ames Salmonella tests; however, one report found enhanced mutagenic activity with a hot-water extract of B. falcatum.
A rat toxicity study investigated three dosages of B. chinense (50, 150, and 300 mg/kg), finding a dose-dependent hepatic tissue damage associated with increased liver enzymes and visible hepatic tissue damage. Bupleurum at a dose of 1 mg/kg for 4 or 8 weeks also increased liver enzymes (AST and ALT), immunoglobulins, and antinuclear antibody in the blood, and elevated interferon-γ, interleukin-10, and transforming growth factor-β1 levels in liver tissues, along with necroinflammatory changes seen with histological sampling.
Drug Interactions
Anti-aggregating effects on platelets by the lactone bupleurumin (extracted from the aerial parts of B. falcatum) have been demonstrated in vitro, suggesting a potential interaction with anticoagulant or antiplatelet drugs, though this has not been confirmed in human studies.
Data suggest caution and close monitoring in patients with hepatitis B who concomitantly use interferon and bupleurum, given reports of elevated liver enzymes, immunoglobulins, and antinuclear antibodies under combined regimens in animal studies.
Further investigations and screenings are required to evaluate the clinical safety and possible interactions with other drugs or herbs. Standardization of Bupleurum extracts is crucial for integration into conventional medicine due to large chemical and biological variations between different species and varieties.
Pregnancy and Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking.
Interspecies Confusion and Quality Concerns
In East Asia, the scientific name Bupleurum falcatum is often misapplied to another species, Bupleurum stenophyllum, which can result in variable or inconsistent product composition. More than 20 species of the genus Bupleurum have been described, including a toxic species, Bupleurum longiradiatum, found in northeast China. Species misidentification in commercial preparations therefore represents a meaningful safety concern. Standardization of Bupleurum extracts is crucial for them being integrated into conventional medicine due to large chemical and biological variations between different species and varieties.
References
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