Ginseng for Liver Injury: Friend or Foe?

Abstract

Introduction

The term ginseng refers to the dried root of the Panax spp. (family Araliaceae), including Panax ginseng Meyer (PG, Asian Ginseng or Korean ginseng), Panax quiquifolius L. (PQ, American Ginseng), and Panax notoginseng (Burk.) FH Chen (PN; Figure 1) [1,2]. These have been used worldwide as herbal medicines or as functional foods. Of them, PG is the most frequently used. Shibata et al. isolated ginseng saponins from PG as bioactive, unique components in 1963, and named them ginsenosides [3,4]. Thereafter, other researchers have isolated approximately 200 components from PG, PQ, and PN, including other ginsenosides, polysaccharides, and polyacetylenes.

The unique components of ginseng are chiefly ginsenosides, which are classified into dammarane-type, ocotillol-type, and oleanane-type oligoglycosides, as well as polysaccharides. Dammarane-type ginsenosides are further classified into two types: protopanaxadiol and protopanaxatriol [4,5]. Ginsengs and their main constituents (ginsenosides and polysaccharides) have been reported to exhibit many pharmacological properties: anti-oxidant, anti-aging, anti-inflammatory, memory-enhancing, anxiolytic, anti-diabetic, and hepatoprotective effects [2,5,6,7]. Most importantly, ginseng extracts have been shown to improve learning and memory in healthy, aged, or brain-damaged animals [8,9]. In particular, ginsenoside Rb1 and 20-O-(β-d-glucopyranosyl)-20(S)-protopanaxadiol (compound K, CK) were reported to be the major players in improving memory disorders, axonal atrophy, and synaptic loss in a mouse model of Alzheimer’s disease (AD) induced by an intracerebroventricular injection of amyloid β peptide (Aβ) (25–35) [10]. PG extract has also been found to restore glucose homeostasis and insulin sensitivity [11], and prevent type 2 diabetes mellitus and possibly obesity in mice through insulin resistance index improvement and diameter decrease in white and brown adipocytes [12]. With regards to diabetes mellitus, ginsenoside Rb2 may inhibit palmitate-induced gluconeogenesis [13,14]. Of the PG polysaccharides, ginsan has been shown to be a potent immunomodulatory agent inducing production of the cytokines: tumor necrosis factor (TNF), interleukin (IL)-1β, IL-2, IL-6, IL-12, interferon (IFN)-γ, and granulocyte-macrophage colony-stimulating factor [15]. Acidic polysaccharides exhibit strong immune-stimulating activity via stimulation of splenic T cell and B cell proliferation, increasing nitric oxide production from peritoneal macrophages, and enhancing natural killer cell activity [16]. Ginseng total saponin can modulate dopaminergic activity at both presynaptic and postsynaptic dopamine receptors [17]. Ginsenoside Rh2 and CK were found to ameliorate ischemic brain injury [18]. Ginsenosides have been demonstrated to lower plasma cholesterol and triglyceride levels, and inhibit aortic atheroma formation in an animal mode of high-cholesterol diet-induced hypercholesterolemia [19]. Ginsenoside Rb1 and CK have been reported to exhibit hepatoprotective effect against tert-butyl hydroperoxide-induced liver injury [20]. Red ginseng (RG, the steamed root of PG) was shown to attenuate ethanol-induced steatosis and oxidative stress [20]. Ginseng has been reported to have a strong anti-cancer effect against many different cancer types; ginsenosides, in particular, have been found to be cytotoxic against various cancer cells. Among them, CK most potently inhibits the growth of cancer cells [21], while PG as an adjuvant can enhance the anti-proliferative effect of chemotherapy [22]. As illustrated above, it is well known that the two key bioactive component groups of ginseng are ginsenosides and polysaccharides; however, the pharmacological effects of polysaccharides have not been studied nearly as extensively as those of ginsenosides.

Ginsengs (PG, PQ, and PN) and their components have been shown to have therapeutic effects against numerous hepatic injuries (Table 1). However, given that there are many bioactive components of ginseng, including the ones yet to be isolated with unknown biological effects, there has been concern regarding the potential adverse interaction between ginseng and other drugs. Thus, this review aims to describe the therapeutic effects of ginseng against many hepatic injuries along with the underlying mechanisms of such therapeutic effects. As the use of herbs including ginseng is increasing, the risk of liver toxicity is also increasing [23]. Therefore, this review will also discuss the potential hepatotoxicity of ginseng to better understand the risk ginseng use poses to the liver.

Conclusions

Ginseng extract and its saponins exhibit hepatoprotective effects against various hepatic injuries caused by chemical substances and hepatitis viruses. These causes of hepatitis produce ROS and activate inflammation signaling pathways such as the NF-κB pathway. Ginseng potently inhibits ROS production and the inflammation-signaling pathway. Moreover, as unique constituents of ginseng, ginsenosides have been found to inhibit liver carcinoma proliferation, promote liver regeneration, and prevent liver ischemia through anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms (Figure 2). Moreover, when used with vitamin or acetaminophen, the ginseng components were observed to exert additive or synergistic effects on hepatic injuries. However, these ginseng components inhibit CYP3A4, leading to serious hepatotoxicity when used with imatinib or raltegravir. In this respect, when a ginseng extract or its component is used clinically along with other drugs, the extract or component needs to be examined carefully to determine if it inhibits a particular CYP450 enzyme responsible for drug metabolism, as it might lead to increased efficacy and ultimately serious hepatotoxicity.

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