Panax 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 12.

Ginseng modulates blood pressure, metabolism and immune functions 3456. The action mechanism of ginseng had not been known until ginsenosides were isolated in 1963 78. 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 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 910. Ginsenosides are named as 'Rx', where the 'R' stands for the root and the 'x' describes the chromatographic polarity in an alphabetical order 7, 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 910. Moreover, several rare ginsenosides, such as the ocotillol saponin F11 (24-R-pseudoginsenoside) 11 and the pentacyclic oleanane saponin Ro (3,28-O-bisdesmoside) 12 have also been identified.

The 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 1314. 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 1516. The overall saponin content in ginseng is directly proportional to its age, reaching a peak level at around 6 years of age 1718. 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 192021222324. The presence of these compounds may confirm the folk knowledge that red ginseng is of higher medicinal values than the white one 25.

Sun 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 2627282930. 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 31.

To 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 323334.

Similar to plants that produce insect repellents and anti-microbial substances as part of their defense mechanisms, e.g. nicotine from tobacco leaves 35, rotenone from derris tree roots 36, pyrethroids from chrysanthemum flowers 37, and triterpenoids from neem tress 38, 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 394041. Naturally occurring ginsenosides are antimicrobial and antifungal; the bitter taste of ginsenosides makes them antifeedant 4243444546.

Furthermore, 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 47 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 47. Such difference, however, has minor and non-significant influence on ecdysteroid receptor binding affinity as demonstrated by biochemical analysis 4748. The structural similarity suggests that certain naturally occurring ginsenosides may disrupt insects' life cycle by binding to ecdysteroid receptor.

Treatment of various cultured cells by ginsenosides revealed multiple bioactivities, including neuroprotection 4950515253, antioxidation 545556, angiogenesis modulation 575859 and cytotoxicity 606162. However, biotransformation may be required before ginsenosides becoming active in mammalian systems. Recent studies demonstrated that ginsenoside metabolites had greater biological effects than ginsenosides 636465. Anti-tumor activities of Rh2 and PD, which are the metabolites of Rg3, are more potent than those of ginsenoside Rg3 64. 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 65.

Major 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 6667686970. 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 7172. The C-3 or C-20 oligosaccharides are also cleaved by intestinal microflora stepwise from the terminal sugar 7273. These intestinal microflora include Prevotella oris 74, Eubacterium A-44 75, Bifidobacterium sp. 7376, Bacteroides JY6 73, Fusbacterium K-60 73, Lactobacillus delbrueckii sp. 76 and Aspergillus sp. 76. Following biodegradation, compound K and protopanaxadiol (PPD) are the major metabolites of PPDs while PPTs are converted to F1 and protopanaxatriol (PPT) (Figure 1).

How 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 777879. The sodium-dependent glucose co-transporter 1 may be involved in this process 80. The availability of intact ginsenosides and their metabolites from the intestines is extremely low 818283. For example, only 3.29% Rg1 and 0.64% Rb1 are detected in rat serum after oral administration of ginsenosides 7879, confirming the classic studies by Odani et al. in 1983 8485. Rg1 levels become undetectable within 24 hours of oral consumption while Rb1 levels remain relatively stable for three days 83.

Experiments to increase the bioavailability of ginsenosides include co-administration of ginsenosides with adrenaline 86, emulsification of ginsenosides into lipid-based formulation 8788 and suppression of p-glycoprotein efflux system 77. 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 288990.

Ginsenosides modulate expressions and functions of receptors such as receptor tyrosine kinases (RTK) 91, serotonin receptors (5-HT) 92, NMDA receptors 93 and nicotinic acetylcholine receptors (AChR) 94. Direct interactions of ginsenosides with the receptor ligand-binding sites have only been demonstrated in steroid hormone receptors; ginsenosides Rg1 589596 and Re 97 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 5998. These findings provide an explanation for the aggravation of menopausal symptoms by ginsenosides 99100 and modulation of the endocrine system in the case of chronic consumption of ginseng 34.

Glucocorticoid 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 9697. Since Rg1 and Re elicit biological activities that are GR inhibitor RU486 sensitive, indicating these ginsenosides are agonists, but not inhibitors for GR 5896. 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 5896. 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.

Moreover, 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 101. Effects of ginsenoside Re on cardiac myocytes are related to ER alpha isoform, androgen receptor and progesterone receptor 102. The end-metabolites PD and PT bind and activate both GR and ER in endothelial cells 103. The multi-target properties of ginsenosides may explain why ginseng has a wide range of beneficial effects.