A Narrative Review Of The Pharmacology Of Ginsenoside Compound K Part 1

Background and Objective: The ginsenoside compound K [20-o-beta-dglucopyranosyl-20 (S)- protopanaxadiol; CK] is the main deglycosylated metabolite of ginsenoside. As a rare ginsenoside converted from the active substance of ginseng by intestinal bacteria, CK has higher biological activity than other ginsenosides. It has demonstrated diverse and intriguing biological activities, including anti-carcinogenic, anti-diabetic, anti-inflammation, anti-allergy, anti-angiogenesis, anti-aging, neuroprotective, and hepatoprotective effects. The purpose of this review was to elucidate the rich pharmacological activities and related mechanisms of ginsenoside CK in vivo and in vitro, as well as the potential therapeutic value of CK as a drug in a variety of systemically related diseases.

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Methods: The PubMed database was searched for articles published in English from February 2008  to December 2021 using related keywords such as“Ginsenoside compound K”, “compound K", and“CK”. About 140 research papers and reports written in English were identified. These papers mainly concentrated on the pharmacological activities of CK in cancer prevention, immune regulation, diabetic improvement, central nervous system (CNS) protection, cardiovascular protection, skin improvement, and hepatoprotection.

Key Content and Findings: This paper describes the synthesis, pharmacokinetics, and adverse reactions of CK, as well as a great detailed summary of the relevant pharmacological activities. Such diverse intriguing biological properties of CK have been found.

Conclusions: On account of CK’s numerous pharmacological activities and anti-carcinogenic, antiinflammation, antiallergic, anti-diabetic, anti-angiogenesis, anti-aging, neuroprotective, and hepatoprotective effects, strong evidence is available for CK as a preventive or therapeutic agent for various diseases. However, further studies are needed to evaluate the safety and effectiveness of CK as a drug and its application in the medical field.

Keywords: Ginsenoside compound K; pharmacology; cancer; diabetes 

Introduction

Ginseng is a traditional Chinese herb with a long history of use in traditional Chinese medicine (TCM). It has powerful tonic effects and is widely used in various medicines (1). With the development of extraction technology, the most pharmacologically active constituents of ginseng have been reported to be ginsenosides, a group of triterpene saponins (2). To date, more than 150 active constituents have been extracted from the roots, stems,   leaves, fruits, and flowers of ginseng (3). Studies have reported that ginsenosides are not absorbed intact in vivo, but need to be metabolized by intestinal microflora before being absorbed through the intestinal tract (4-6). Other studies have shown that deglycosylation is the major metabolic pathway involved in the transformation of ginsenosides to deglycosylated ginsenosides, which have higher biological activity than ginsenosides (7,8). Compound K (CK, 20-o-beta-d-glucopyranosyl-20 (S)- protopanaxadiol, C36H62O8) is the major deglycosylated metabolite of ginsenoside (8). Recent in vivo and in vitro studies have reported that CK is involved in multiple pharmacological processes and possesses anticarcinogenic (9), anti-diabetic (10), anti-inflammatory (11),   anti-allergic (12), anti-angiogenic (13), anti-aging (14), and hepatoprotective effects (15), as well as effects on the central nervous system (CNS) (16). In particular,   many studies have investigated its pharmacological effects. However, no study has investigated the complete integration of the pharmacological activity of CK.  Therefore, we reviewed the pharmacological activity and associated mechanisms of CK in detail and updated the literature in recent years. It is expected to help develop potential agents to treat related diseases.

Methods

The PubMed database was searched for articles published in English from February 2008 to May 2021 using related keywords such as “Ginsenoside compound K”, “compound  K”, and “CK”. The information used to write this paper was collected from the sources listed in Table 1.

Biotransformation, pharmacokinetics, and safety of CK

The ginsenoside CK belongs to the family of tetracyclic dammarane-type triterpenoid saponins. Based on their chemical structure, dammarane group ginsenosides are classified into two types: protopanaxadiol (PPD), which includes Ra1, Ra2, Ra3, Rb1, Rb2, Rb3, Rc, Rd, Rg3, Rh2,  F2, and CK, and protopanaxatriol (PPT), which includes  Re, Rf, Rg1, Rg2, Rh1, and F1 (Figure 1) (17,18).

Japanese researchers originally isolated CK from a mixture of Rb1, Rb2, and Rc, which were hydrolyzed from ginseng by a soil bacterium (19). Although its structure was identified in 1972, the finding that Rb1 and Rb2 were metabolized into CK by intestinal bacteria in rats via a specific pathway was reported 20 years later (20,21). Hasegawa et al. (22,23) investigated the specific transformation pathway of CK by intestinal microflora and speculated that CK was the most likely form of protopanaxadiol saponins that underwent intestinal absorption. The specific metabolic pathways of Rb1 and  Rb2 metabolism to CK by intestinal bacteria are shown in  Figure 2 (23,24). After the oral administration of Rb1 to rats, a high concentration of CK, but no Rb1, was found to be present in their intestinal contents, plasma, and urine (25-27). Researchers have focused on the biological functions of CK and methodology for the effective production of CK from major ginsenosides.

The bioavailability of ginsenosides without transformation and modification suggests low absorption in the intestinal tract (28,29). After the oral administration of ginsenosides, a series of biological transformations occur in the intestinal tract, and they are converted into deglycosylated metabolites with higher biological activities than their precursor compounds (7). Other studies have reported that intestinal bacteria or soil fungi around ginseng roots, as well as some microorganisms, hydrolyze ginsenosides to form CK (30,31). The various methods for microbial conversion are summarized in Table 2 (7).

The enzyme β-glucosidase, with a molecular weight of 320 kDa and 4 identical subunits (80 kDa), is a key enzyme in the hydrolysis of Rb1 into CK (45) and was initially purified from metabolizing bacteria isolated from human intestinal feces (46). Subsequently, β-glucosidase that promoted more specific and effective transformation was found and purified in the soil of ginseng fields (47,48). Later, researchers extracted β-glycosidase from Sulfolobus solfataricus and other acid-resistant hot microbiota, and its degree of transformation and efficiency were higher than those previously reported (49-51). Subsequent studies focused on the activity and conversion efficiency associated with the design and modification of enzymes (45,52,53).  Shin et al. (45) designed W361f, a variant of β-glycosidase,   which had 4.2 times the activity of Rd, 3.7 times higher catalytic efficiency, and 3.1 times lower binding energy than the wild-type enzyme. They also found that semi-rational design was a useful tool to enhance the hydrolytic activity of β-glycosidase. Therefore, it is important to discover and modify catalytic enzymes to improve the utilization and production efficiency of CK (54).

As intestinal microflora is important for the biotransformation and pharmacological activity of CK, it is necessary to study the metabolic pathways that regulate intestinal microflora. Recent studies have indicated that Western dietary habits and NUTRIOSE (ROQUETTE  Frères, Lestrem, France) were more likely to improve the concentration level of CK (55,56). Furthermore, a study of human metabolism found that a high-fat diet significantly accelerated and increased the absorption of CK and that the concentration level of CK in women was higher than that in men (57). A randomized double-blind study reported the gender- and food-related impacts on CK pharmacokinetics (58).

Another pharmacokinetic study of CK reported the drug levels in blood samples of 10 healthy men 36 hours after the administration of Korean ginseng extract (59).  The mean maximum plasma concentration (Cmax) of CK was significantly higher than the level of Rb1 (8.35±3.19 vs. 3.94±1.97 ng/mL) and the mean time to reach the Cmax (Tmax) of CK was longer than that of Rb1 (12.20±1.81 vs. 8.70±2.63 h). The delay in the absorption of CK supports the idea that intestinal microflora transforms Rb1 to CK. The plasma half-life (t1/2) of CK was 7 times shorter than that of Rb1. These results indicate that the pharmacokinetics of CK are significantly different from those of Rb1. In another study (58), 76 participants received CK or placebo in 7 single oral doses (25, 50, 100,  200, 400, 600, 800 mg) while fasting; the time range to reach Tmax was 1.5–6.0 h, and the exposure to CK increased linearly in the range of 100 to 400 mg. The steady state was reached after the seventh administration and no severe adverse events (AEs) were observed. The most reported AEs were watery stool (diarrhea) and bellyache, and all AEs were mild or moderate, most of them were disappeared or reversible without any treatment (57,58).  These results indicated that CK was safe and well tolerated over the treatment period.

In a toxicity study, the oral administration of CK to rats and mice did not cause death or toxicity at the maximum doses of 8 and 10 g/kg, respectively (60). In a 26-week   toxicity study, rats were administered CK at doses of  13, 40, or 120 mg/kg and observed at 26 weeks and 4-week recovery periods. Compared with the control group, asthenia, fur-loss, hypoactivity, and body weight reduction were observed in the 120 mg/kg male rat group, the hepatotoxicity, and nephrotoxicity including elevated serum  ALT and ALP, higher liver relative weight with similar histological changes to the 90-day sub-chronic intravenous  CK in rat, and higher kidney relative weight with no histological changes were also shown in 120 mg/kg male rat group, but the toxicity was reversible after 4-week recovery. No abnormalities in routine activity, laboratory markers, and histopathological examination were found in the 13 and 40 mg/kg CK groups (60). In addition, the no observed harmful effect level was 40 mg/kg in males and  120 mg/kg in female rats. In a beagle toxicity study, animals in the 36 mg/kg group showed reversible hepatotoxicity and significant weight loss during the study period. Animals in the 4 and 12 mg/kg groups did not show any significant toxicity (61).

CK is safe and well-tolerated in animal and human subjects. These preclinical results suggest that the liver may be a toxic organ for CK.  Although the relative weight of the kidney was high, there was no histological change, but nephrotoxicity should be noted. CK-related AEs in clinical trials were diarrhea and abdominal pain. Drug-related AEs are common for drug-induced diarrhea. There are few clinical trials on CK and few reports on CK-related AEs. Therefore, further studies are needed to investigate the mechanisms of CK-induced toxicity, especially hepatotoxicity, and GCK-induced gastrointestinal tract.

Pharmacological properties of CK

The numerous pharmacological effects of CK, including cancer prevention (62), immune regulation (63),   diabetic improvement (64), CNS protection (65), cardiovascular protection (66), skin improvement (67), and hepatoprotection (68) have been demonstrated in vitro and in vivo using animal models. The detailed pharmacological effects of CK are discussed below. The major functions and action targets of CK are summarized in Table 3,4.

Anticarcinogenic effects of CK

The number of cancer patients is increasing annually; however, an effective cancer treatment is still lacking and no specific drug can cure cancer (138). Thus, the identification of new therapeutic drugs for cancer is urgent. The antitumor effects of CK are different in vivo and in vitro.  Several studies have reported the cytotoxic and growth-inhibiting effects of CK on tumor cells, whereas other studies have reported that CK inhibits tumor cell metastasis and tumor growth (70,79,87,88,90,139). Therefore, CK   may be a potentially important anticancer drug. 

Inhibition of tumor growth by CK

In an in vivo study, CK significantly inhibited the growth of nasopharyngeal carcinoma (HK-1) tumors (91). On the 5th day after treatment, the tumor size in the CK-treated group was 25.6% smaller than that in the control group (91). Also, CK dose-dependently reduced the tumor growth of colorectal cancer (HCT-116) (79) and significantly inhibited tumor growth in an athymic nude mouse xenograft model of colorectal cancer cells (HCT- 116, SW-480, HT-29). At 3 weeks after CK treatment;   the high-dose group (30 mg/kg) had a stronger antitumor effect compared with the low-dose group (15 mg/kg), which was dose- and time-dependent (77). These studies suggested that CK might prevent or treat colorectal cancer (77). Furthermore, CK inhibited the growth and colony formation of cancer cells in mice transplanted with human liver cancer cells and boosted the anti-tumor effect of gamma rays in a nude mouse xenograft human lung cancer cell (NCI-H460) model, indicating that it might be an adjuvant of radiotherapy for tumor treatment (71,74).

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