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Pharmacology of ginsenosides: a literature review

Kar Leung, Alice Wong

Chinese Medicine · 2010 · Review

Abstract

The therapeutic potential of ginseng has been studied extensively, and ginsenosides, the active components of ginseng, are shown to be involved in modulating multiple physiological activities. This article will review the structure, systemic transformation and bioavailability of ginsenosides before illustration on how these molecules exert their functions via interactions with steroidal receptors. The multiple biological actions make ginsenosides as important resources for developing new modalities. Yet, low bioavailability of ginsenoside is one of the major hurdles needs to be overcome to advance its use in clinical settings.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Background

1Panax ginseng (Renshen, Chinese ginseng) is commonly used either by itself or in combination with other medicinal ingredients as a key herb in Chinese medicine. A member of the Araliaceae family, the genus name Panax was derived from the Greek word meaning "all-healing" first coined by the Russian botanist Carl A. Meyer. The Panax family consists of at least nine species, including P. ginseng, Panax quinquefolium (Xiyangshen, American ginseng), Panax notoginseng (Sanqi) and Panax japonicus (Japanese ginseng). The worldwide sale of ginseng products has estimated to reach US$ 300 million in 2001.

2Ginseng modulates blood pressure, metabolism and immune functions. The action mechanism of ginseng had not been known until ginsenosides were isolated in 1963. Much effort has since been focused on evaluating the function and elucidating the molecular mechanism of each ginsenoside. Number of publications on ginseng and ginsenosides has been growing exponentially since 1975 according to the Pubmed entry.

Ginsenosides are the pharmacologically active components in ginseng

3Ginsenosides are triterpene saponins. Most ginsenosides are composed of a dammarane skeleton (17 carbons in a four-ring structure) with various sugar moieties (e.g. glucose, rhamnose, xylose and arabinose) attached to the C-3 and C-20 positions. Ginsenosides are named as 'Rx', where the 'R' stands for the root and the 'x' describes the chromatographic polarity in an alphabetical order, for example, Ra is the least polar compound and Rb is more polar than Ra. Over 30 ginsenosides have been identified and classified into two categories: (1) the 20(S)-protopanaxadiol (PPD) (Rb1, Rb2, Rb3, Rc, Rd, Rg3, Rh2, Rs1) and (2) the 20(S)-protopanaxatriol (PPT) (Re, Rf, Rg1, Rg2, Rh1). The difference between PPTs and PPDs is the presence of carboxyl group at the C-6 position in PPDs. Moreover, several rare ginsenosides, such as the ocotillol saponin F11 (24-R-pseudoginsenoside) and the pentacyclic oleanane saponin Ro (3,28-O-bisdesmoside) have also been identified.

4The quality and composition of ginsenosides in the ginseng plants are influenced by a range of factors bhsuch as the species, age, part of the plant, cultivation method, harvesting season and preservation method. For example, ginsenoside Rf is unique to Asian ginseng while F11 is found exclusively in American ginseng. Thus the Rf/F11 ratio is used as a phytochemical marker to distinguish American ginseng from Asian ginseng. The overall saponin content in ginseng is directly proportional to its age, reaching a peak level at around 6 years of age. Most harvested ginseng roots are air-dried while some are steamed at 100°C for two to four hours before drying, which gives the ginseng a darker appearance known as red ginseng. The red ginseng has a unique saponin profile, with emerging ginsenosides Ra1, Ra2, Ra3, Rf2, Rg4, Rg5, Rg6, Rk1, Rs1 and Rs2 being likely the results of heat transformation and deglycosylation of naturally occurring ginsenosides. The presence of these compounds may confirm the folk knowledge that red ginseng is of higher medicinal values than the white one.

5Sun ginseng is a new type of processed ginseng that is steamed at 120°C. The new process aimed to increase the levels of anti-tumor ginsenosides Rg3, Rg5 and Rk1. Moreover, the butanol-soluble fraction of Sun ginseng is formulated into KG-135 which contains Rk3 Rs3, Rs4, Rs5, Rs6 and Rs7 in addition to the major anti-tumor ginsenosides.

Standardized ginseng extracts

6To avoid variability among preparations, many researchers use commercially available standardized ginseng extracts. Two commonly used standardized extracts are G115 from P. ginseng (total ginsenoside adjusted to 4%) (Pharmaton SA, Switzerland) and NAGE from P. quinquefolius (total ginsenoside content adjusted to 10%) (Canadian Phytopharmaceuticals Corporation, Canada). Studies on these two ginseng extracts using high-performance liquid chromatography (HPLC) found ginsenosides Rb1, Rb2, Rc, Rd, Re and Rg1 in both G115 and NAGE, and ginsenoside Rg2 in G115 only. To compare between G115 and NAGE, G115 has higher Rg1, but NAGE has higher in Rb1 and Re.

Ginsenosides are part of the defense mechanisms in ginseng

7Similar to plants that produce insect repellents and anti-microbial substances as part of their defense mechanisms, e.g. nicotine from tobacco leaves, rotenone from derris tree roots, pyrethroids from chrysanthemum flowers, and triterpenoids from neem tress, evidence suggests that ginsenosides may protect ginseng. Addition of methyl jasmonate (a plant-specific signaling molecule expressed during insect and pathogenic attacks) into ginseng in vitro cultures enhances ginsenoside production. Naturally occurring ginsenosides are antimicrobial and antifungal; the bitter taste of ginsenosides makes them antifeedant.

8Furthermore, ginsenosides may act as ecdysteroids, the insect molting and metamorphosis hormones, due to the structural similarities between the two groups of chemicals. The ecdysteroids have a steroid backbone with a C-20 sugar side-chain and a C-3 hydroxyl group resembling the structure of most of the PPT-type ginsenosides such as Rg1 and several metabolites of PPDs such as compound Y and compound K. Ecdysteroids differ from ginsenosides in the C-6 position which is occupied by an oxygen group is in the former and a hydrogen or hydroxyl group in the latter. Such difference, however, has minor and non-significant influence on ecdysteroid receptor binding affinity as demonstrated by biochemical analysis. The structural similarity suggests that certain naturally occurring ginsenosides may disrupt insects' life cycle by binding to ecdysteroid receptor.

Biotransformation of ginsenosides

9Treatment of various cultured cells by ginsenosides revealed multiple bioactivities, including neuroprotection, antioxidation, angiogenesis modulation and cytotoxicity. However, biotransformation may be required before ginsenosides becoming active in mammalian systems. Recent studies demonstrated that ginsenoside metabolites had greater biological effects than ginsenosides. Anti-tumor activities of Rh2 and PD, which are the metabolites of Rg3, are more potent than those of ginsenoside Rg3. Ginsenosides Rb1, Rb2, Rg1 and Re do not possess the same human liver enzyme cytochrome P450 inhibitory effects of compound K, PT and PD which are the intestinal metabolites of PPTs and PPDs.

10Major ginsenosides, such as Rg1, Rg3, Rb1, Re and Rc, are treated as antigens by mammalian systems. Antibodies against these ginsenosides have been purified from immunized animals. Due to their bulky molecular structures, the ginsenosides are poorly membrane permeable and prone to degradation. Oral consumption of ginseng preparations exposes ginsenosides to acid hydrolysis accompanied by side-reactions, glycosyl elimination and epimerization of C-20 sugar moiety. The C-3 or C-20 oligosaccharides are also cleaved by intestinal microflora stepwise from the terminal sugar. These intestinal microflora include Prevotella oris, Eubacterium A-44, Bifidobacterium sp., Bacteroides JY6, Fusbacterium K-60, Lactobacillus delbrueckii sp. and Aspergillus sp.. Following biodegradation, compound K and protopanaxadiol (PPD) are the major metabolites of PPDs while PPTs are converted to F1 and protopanaxatriol (PPT) (Figure 1).

Pharmacokinetic and bioavailability of ginsenosides

11How intact and transformed ginsenosides are absorbed and transported to the human system remains elusive. Transport of ginsenosides across the intestinal mucosa is energy-dependent and non-saturable. The sodium-dependent glucose co-transporter 1 may be involved in this process. The availability of intact ginsenosides and their metabolites from the intestines is extremely low. For example, only 3.29% Rg1 and 0.64% Rb1 are detected in rat serum after oral administration of ginsenosides, confirming the classic studies by Odani et al. in 1983. Rg1 levels become undetectable within 24 hours of oral consumption while Rb1 levels remain relatively stable for three days.

12Experiments to increase the bioavailability of ginsenosides include co-administration of ginsenosides with adrenaline, emulsification of ginsenosides into lipid-based formulation and suppression of p-glycoprotein efflux system. P-glycoprotein-mediated multidrug resistance is a major obstacle to effective cancer treatments. As ginsenoside Rg3 blocks drug efflux by inhibiting p-glycoprotein activities and reducing membrane fluidity, it is used to assist cancer chemotherapy.

Ginsenosides are agonists to steroidal receptors

13Ginsenosides modulate expressions and functions of receptors such as receptor tyrosine kinases (RTK), serotonin receptors (5-HT), NMDA receptors and nicotinic acetylcholine receptors (AChR). Direct interactions of ginsenosides with the receptor ligand-binding sites have only been demonstrated in steroid hormone receptors; ginsenosides Rg1 and Re are functional ligands of the glucocorticoid receptor (GR) while ginsenosides Rh1 and Rb1 are functional ligands of the estrogen receptor (ER), in particular, the ER beta isoform of Rb1. These findings provide an explanation for the aggravation of menopausal symptoms by ginsenosides and modulation of the endocrine system in the case of chronic consumption of ginseng.

14Glucocorticoid is a stress hormone to elicit 'fight-or-flight' responses through GR activation. If Rg1 and Re are functional ligands of GR, how is ginseng adaptogenic and antistress? Rg1 and Re may behave as partial agonists to GR. Both Rg1 and Re inhibit the binding of the synthetic glucocorticoid dexamethasone to GR and 100% displacement is possible when ginsenosides are in excess. Since Rg1 and Re elicit biological activities that are GR inhibitor RU486 sensitive, indicating these ginsenosides are agonists, but not inhibitors for GR. And it is because the steroidal effects of Rg1 and Re are not as prominent as dexamethasone, these ginsenosides are likely to be partial agonist of GR. Under physiological conditions, ginsenosides may compensate the insufficient steroidal activities, when the intrinsic ligand is absent or inadequate in the system. On the other hand, ginsenosides can reversibly occupy certain percentage of the steroidal receptor at low affinity to counter the steroidal effects when they co-exist with a large amount of intrinsic ligand.

15Moreover, each ginsenoside is able to bind to multiple steroid hormone receptors. In addition to GR, ginsenoside Rg1 acts through ER and elicits cross-talking with insulin-like growth factor-1 receptor (IGF-IR) in neuronal cells. Effects of ginsenoside Re on cardiac myocytes are related to ER alpha isoform, androgen receptor and progesterone receptor. The end-metabolites PD and PT bind and activate both GR and ER in endothelial cells. The multi-target properties of ginsenosides may explain why ginseng has a wide range of beneficial effects.

Conclusion

16As partial agonists to multiple steroidal receptors, ginsenosides are important natural resources to be developed into new modalities, and may replace steroids in the current regimen to lessen undesirable side effects. However, low bioavailablilities of ginsenosides and its metabolites means that most of these compounds do not reach the intended biological system when administered orally. The results of ginsenoside researches will become physiological relevant only when (1) the pure compounds of the ginsenosides is available in large quantities; (2) the ginsenosides are biochemically stabilized to avoid degradation and enhance absorption in the gastrointestinal tract; and/or (3) special delivery methods for the ginsenosides to reach the areas of treatment. Moreover, this review highlighted the necessary of ginsenoside transformation to exert its greatest effects in the mammalian system, thus accelerating this process would help maximizing the remedial effects of ginsenosides. Addressing these two issues in the near future would advance ginseng researches and enhance the possibility for ginseng to be used clinically.

Abbreviations

175-HT: serotonin receptors; AChR: acetylcholine receptor; ER: estrogen receptor; GR: glucocorticoid receptor; HPLC: high performance liquid chromatography; IGF-IR: insulin-like growth factor-1; PD: panaxadiol; PT: panaxatriol; PPD: 20(S)-protopanaxadiol; PPT: 20(S)-protopanaxatriol; RTK: receptor tyrosine kinases

Competing interests

18The authors declare that they have no competing interests.

Authors' contributions

19KWL and ASTW contributed equally on developing the concept, drafting and editing the manuscript. Both authors read and approved the final version of the manuscript.

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Bae EA Choo MK Park EK Park SY Shin HY Kim DH Metabolism of ginsenoside Re by human intestinal bacteria and its related antiollergic activityBiol Pharm Bull2002 25743747
Not in our library10.1248/bpb.25.743
74.
Hasegawa H Sung JH Benno Y Role of human intestinal Prevotella oris in hydrolyzing ginseng saponinsPlanta Med1997 63436440
Not in our library10.1055/s-2006-957729
75.
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Not in our library10.1111/j.2042-7158.1998.tb03327.x
76.
Chi H Kim DH Ji GE Transformation of ginsenoside Rb2 and Rc from Panax ginseng by food microorganismsBiol Pharm Bull2005 2821022105
Not in our library10.1248/bpb.28.2102
77.
Xie HT Wang GJ Chen M Jiang XL Li H Lv H Huang CR Wang R Roberts M Uptake and metabolism of ginsenoside Rh2 and its aglycon protopanaxadiol by Caco-2 cellsBiol Pharm Bull2005 28383386
Not in our library10.1248/bpb.28.383
78.
Han M Fang XL Difference in oral absorption of ginsenoside Rg1 between in vitro and in vivo modelsActa Pharmacol Sin2006 27499505
Not in our library10.1111/j.1745-7254.2006.00303.x
79.
Han M Sha X Wu Y Fang X Oral absorption of ginsenoside Rb1 using in vitro and in vivo modelsPlanta Med2006 72398404
Not in our library10.1055/s-2005-916211
80.
Xiong J Sun M Guo J Huang L Wang S Meng B Ping Q Active absorption of ginsenoside Rg1 in vitro and in vivo: the role of sodium-dependent glucose co-transporter 1J Pharm Pharmacol2009 61381386
Not in our library10.1211/jpp/61.03.0014
81.
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Not in our library10.1248/cpb.38.2859
82.
Takino Y Studies on pharmacodynamics of ginsenoside-Rg1, Rb1 and -Rb2 in ratsYakugaku Zasshi1994 114550564
Not in our library
83.
Xu QF Fand XL Chen DF Pharmacokinetics and bioavailability of ginsenoside Rb1 and Rg1 from Panax notoginseng in ratsJ Ethnopharmcol2003 84187192
Not in our library10.1016/s0378-8741(02)00317-3
84.
Odani T Tanizawa H Takino Y Studies on the absorption, distribution, excretion and metabolism of ginseng saponins. II. The absorption, distribution and excretion of ginsenoside Rg1 in the ratChem Pharm Bull (Tokyo)1983 31292298
Not in our library10.1248/cpb.31.292
85.
Odani T Tanizawa H Takino Y Studies on the absorption, distribution, excretion and metabolism of ginseng saponins. III. The absorption, distribution and excretion of ginsenoside Rb1 in the ratChem Pharm Bull (Tokyo)1983 3110591066
Not in our library10.1248/cpb.31.1059
86.
Xiong J Sun M Guo J Huang L Wang S Meng B Ping Q Enhancement by adrenaline of ginsenoside Rg1 transport in Caco-2 cells and oral absorption in ratsJ Pharm Pharmacol2009 61347352
Not in our library10.1211/jpp/61.03.0009
87.
Xiong J Guo J Huang L Meng B Ping Q The use of lipid-based formulations to increase the oral bioavailability of Panax notoginseng saponins following a single oral gavage to ratsDrug Dev Ind Pharm2008 346572
Not in our library10.1080/03639040701508292
88.
Han M Fu S Gao JQ Fang XL Evaluation of intestinal absorption of ginsenoside Rg1 incorporated in microemulison using parallel artificial membrane permeability assayBiol Pharm Bull2009 3210691074
Not in our library10.1248/bpb.32.1069
89.
Kim SW Kwon HY Chi DW Shim JH Park JD Lee YH Pyo S Rhee DK Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg3Biochem Pharmacol2003 657582
Not in our library10.1016/s0006-2952(02)01446-6
90.
Kwon HY Kim EH Kim SW Kim SN Park JD Rhee DK Selective toxicity of ginsenoside Rg3 on multidrug resistant cells by membrane fluidity modulationArch Pharm Res2008 31171177
Not in our library10.1007/s12272-001-1137-y
91.
Salim KN McEwen BS Chao HM Ginsenoside Rb1 regulates ChAT, NGF and trkA mRNA expression in the rat brainMol Brain Res1997 47177182
Not in our library10.1016/s0169-328x(97)00042-9
92.
Choi S Lee JH Oh S Rhim H Lee SM Nah SY Effects of ginsenoside Rg2 on the 5-HT3A receptor-mediated ion current in Xenopus oocytesMol Cells15108113
Not in our library
93.
Kim HS Hwang SL Oh S Ginsenoside Rc and Rg1 differentially modulate NMDA receptor subunit mRNA levels after intracerebroventricular infusion in ratsNeurochem Res2000 2511491154
Not in our library10.1023/a:1007634432095
94.
Choi S Jung SY Lee JH Sala F Criado M Mulet J Valor LM Sala S Engel AG Nah SY Effects of ginsenosides, active components of ginseng, on nicotinic acetylcholine receptors expressed in Xenopus oocytesEur J Pharmacol2002 4423745
Not in our library10.1016/s0014-2999(02)01508-x
95.
Lee YJ Chung E Lee KY Lee YH Huh B Lee SK Ginsenoside-Rg1, one of the major active molecules from Panax ginseng, is a functional ligand of glucocorticoid receptorMol Cell Endocrinol1997 133135140
Not in our library10.1016/s0303-7207(97)00160-3
96.
Leung KW Cheng YK Mak NK Chan KKC Fan TPD Wong RNS Signaling pathway of ginsenoside-Rg1 leading to nitric oxide production in endothelial cellsFEBS Lett2006 58032113216
Not in our library10.1016/j.febslet.2006.04.080
97.
Leung KW Leung FP Huang Y Mak NK Wong RNS Non-genomic effects of ginsenoside-Re in endothelial cells via glucocorticoid receptorFEBS Lett2007 58124232428
Not in our library10.1016/j.febslet.2007.04.055
98.
Lee YJ Jin YR Lim WC Ji SM Choi S Jang S Lee SK A ginsenoside-Rh1, a component of ginseng saponin, activates estrogen receptor in human breast carcinoma MCF-7 cellsJ Steroid Biochem Mol Biol2003 84463468
Not in our library10.1016/s0960-0760(03)00067-0
99.
Amato P Christophe S Mellon PL Estrogenic activity of herbs commonly used as remedies for menopausal symptomsMenopause2002 9145150
Not in our library10.1097/00042192-200203000-00010
100.
Liu J Burdette JE Xu H Gu C van Breemen RB Bhat KPL Booth N Constantinou AI Pezzuto JM Fong HHS Farnsworth NR Bolton JL Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptomsJ Agric Food Chem2001 4924722479
Not in our library10.1021/jf0014157
101.
Gao QG Chen WF Xie JX Wong MS Ginsenoside Rg1 protects against 6-OHDA-induced neurotoxicity in neuroblastoma SK-N-SH cells via IGF-I receptor and estrogen receptor pathwaysJ Neurochem2009 10913381347
Not in our library10.1111/j.1471-4159.2009.06051.x
102.
Furukawa T Bai CX Kaihara A Ozaki E Kawano T Nakaya Y Awais M Sato M Umezawa Y Kurokawa J Ginsenoside Re, a main phytosterol of Panax ginseng, activates cardiac potassium channels via a nongenomic pathway of sex hormonesMol Pharmacol2006 7019161924
Not in our library10.1124/mol.106.028134
103.
Leung KW Leung FP Mak NK Tombran-Tink J Huang Y Wong RNS Protopanaxadiol and protopanaxatriol bind to glucocorticoid and oestrogen receptors in endothelial cellsBr J Pharmacol2009 156626637
Not in our library10.1111/j.1476-5381.2008.00066.x

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