Arctigenin (AR) and its glycoside, arctiin, are two major active ingredients of Arctium lappa L (A lappa), a popular medicinal herb and health supplement frequently used in Asia. In the past several decades, bioactive components from A lappa have attracted the attention of researchers due to their promising therapeutic effects. In the current article, we aimed to provide an overview of the pharmacology of AR and arctiin, focusing on their anti-inflammatory effects, pharmacokinetics properties and clinical efficacies. Compared to acrtiin, AR was reported as the most potent bioactive component of A lappa in the majority of studies. AR exhibits potent anti-inflammatory activities by inhibiting inducible nitric oxide synthase (iNOS) via modulation of several cytokines. Due to its potent anti-inflammatory effects, AR may serve as a potential therapeutic compound against both acute inflammation and various chronic diseases. However, pharmacokinetic studies demonstrated the extensive glucuronidation and hydrolysis of AR in liver, intestine and plasma, which might hinder its in vivo and clinical efficacy after oral administration. Based on the reviewed pharmacological and pharmacokinetic characteristics of AR, further pharmacokinetic and pharmacodynamic studies of AR via alternative administration routes are suggested to promote its ability to serve as a therapeutic agent as well as an ideal bioactive marker for A lappa.
Arctigenin (AR) (Figure 1), a phenylpropanoid dizbenzylbutyrolactone lignan, was first identified in Arctium lappa L (A lappa), a popular medicinal herb and health supplement frequently used for anti-influenza treatment in Asia, especially China, Korea and Japan. AR and its glycoside, arctiin, are listed as both the chemical marker compounds and major active ingredients of Fructus Arctii in Chinese Pharmacopeia1. In the past several decades, bioactive components from A lappa, especially AR, have attracted the attention of researchers due to their promising therapeutic effects on inflammation2,3,4, infection5,6,7, metabolic disorders8,9,10, and central nervous system dysfunctions11,12,13.
AR and arctiin have been extensively studied for their anti-inflammatory effects in both in vitro and in vivo models. Inflammation is a series of protective responses of the body against exogenous pathogens and to repair tissue damage resulting from infection or trauma. Acute inflammation is characterized by vasodilatation, fluid exudation and neutrophil infiltration14. Severe inflammation can cause organ injury, shock and even death, presenting major management problems14. Furthermore, when the inflammatory response does not eradicate the primary stimulus, a chronic form of inflammation ensues and contributes to further tissue damage. A number of chronic diseases, including atherosclerosis, cancer, type II diabetes, and Alzheimer's disease, have a pathophysiologically important inflammatory component15. Therefore, developing novel compounds targeting the inflammatory response can be beneficial for the treatment of acute inflammation and infection, as well as many widespread chronic diseases. Studies on the pharmacology of AR and arctiin as natural compounds with significant anti-inflammatory effects may contribute to the development of novel anti-inflammatory therapeutics.
Pharmacokinetic profiles, including the absorption, distribution, metabolism and excretion properties, determine the efficacy and safety of a potential therapeutic. Extensive in vitro and in vivo studies have been conducted on AR and arctiin to elucidate their absorption, metabolite profiles, and plasma concentration profiles, as well as the mechanisms involved. The results of these studies provide comprehensive data on the pharmacokinetic properties of AR and arctiin, leading to further optimization strategies for the use of these natural compounds as potential anti-inflammatory therapeutics.
Although research interest in AR, arctiin and A lappa has been growing rapidly, there are few published review articles on their pharmacological characteristics. In the current article, we aim to provide an overview of the pharmacology of AR and arctiin, especially their anti-inflammatory effects, pharmacokinetics properties and clinical efficacy.
Distribution of AR and arctiin in plants
AR and arctiin belong to the family of lignans, which is a class of phytoestrogens characterized by their dibenzylbutane skeleton. Lignans were first identified in plants and are believed to play a role in the construction of plant cell wall as the precursor of lignin. The contents of AR and arctiin, as well as the total lignans, were found to be the highest in the fruit of A lappa among all the plant parts16. AR and arctiin account for approximately 0.5%–2% (w/w) and 2%–10% (w/w) of the dry weight of the fruit, respectively, depending on place of origin, processing methods, and other factors17,18. AR is regarded as marker compound in dozens of other medicinal herbs, probably due to its promising therapeutic activities19,20. AR and arctiin have been identified in not only A lappa but also more than 38 other plant species, among which 71% belong to the Asteraceae family. Table 1 summarizes the distribution of AR and arctiin in different plant species from eight families, including Aspleniaceae, Asteraceae, Convolvulaceae, Linaceae, Oleaceae, Styracaceae, Taxacea, and Thymelaeaceae. In the family Asteraceae, Centaurea is a genus that includes many AR- and arctiin-containing plants, although the AR and arctiin contents are lower than that in A lappa. Fruits and seeds had high levels of AR and arctiin2,21, while the other parts, such as flower, leaves, stem, and roots, had low levels (Table 1). As shown in Table 1, many of these AR- and arctiin-containing plants are recorded as medical plants in their growing areas and are well-recognized for the treatment of diseases, such as rheumatic arthritis, inflammatory diseases, infection, and others.
Effect of AR and arctiin against inflammatory diseases
Effect of AR and arctiin on acute inflammation and its mechanism
Multiple studies have found that A lappa exhibits anti-inflammatory activities, which were attributed to AR in most research focusing on the traditional Chinese herb22,23,24. The anti-inflammatory effect and the reported mechanism of AR are summarized in Table 2.
The anti-inflammatory effects of AR were demonstrated in various disease models, including local edema, colitis, acute lung injury, and brain trauma. AR was effective in relieving symptoms such as writhing response, capillary permeability accentuation, and edema volume in local tissue inflammation of rats induced by various stimulators25. Protective effects of AR against LPS-induced acute lung injury through suppression of MAPK, HO-1, and iNOS signaling was observed26,27. Furthermore, AR reduced the infiltration of leukocytes into local tissues, a typical hallmark of acute inflammation. This was observed in various colitis mouse models by the decreased activity of myeloperoxidase (MPO), eosinophil peroxidase (EPO), and cluster of differentiation 68 (CD68), indicators of neutrophils, eosinophils and macrophages, respectively2,26,28. In addition, AR reduced brain water content and hematoma and accelerated wound closure in convection-enhanced delivery induced brain injury in mice through regulation of various inflammatory factors and numbers of MPO-positive cells28.
The anti-inflammatory effect of AR was first shown to be mediated through the suppression of NO production via inhibition of inducible nitric oxide synthase (iNOS) at both the expression and activity levels. These findings have been confirmed in multiple in vitro studies that were primarily conducted on a lipopolysaccharide (LPS)-induced inflammatory model of RAW264.7 cells22,29,30,31,32, an immortalized murine macrophage cell line, and on U937 cells22, a human pro-macrophage cell line. The modulatory effects of AR on cyclooxygenase-2 (Cox-2)31,33 have also been reported, but there is controversy regarding the effect of AR on Cox-2. Although both studies were carried out on the same LPS-induced RAW 267.4 cells, Zhao et al reported that AR did not affect Cox-2 expression or enzyme activity at 3–100 μmol/L31, whereas Lee et al found that 0.1 μmol/L of AR could decrease COX-2 expression and PGE2 production by 26.70%±4.61% and 32.84%±6.51%, respectively33. Other in vitro anti-inflammatory effects of AR include inhibition of LPS-induced primary murine splenocyte proliferation22, inhibition of anti-CD3/CD28 antibody-induced primary human T lymphocyte proliferation3, and polarization of M1 macrophages to M2-like macrophages2. The anti-inflammatory effect was also confirmed on silica-induced and peptidoglycan-induced inflammatory cell models25. In addition, AR was reported to have immunomodulatory effects towards type I–IV allergic inflammation34, as well as inhibiting mast cell-mediated allergic responses35.
Molecular mechanisms accounting for the anti-inflammatory effect of AR have been widely investigated in the past decade. Generally, upon sensing infection or tissue damage, transcription factors such as nuclear factor κB (NF-κB) are activated to induce the expression of genes participating in the inflammatory response (eg, iNOS and COX-2). Cytokine-mediated feed-forward loops can amplify and coordinate this inflammatory response15. The anti-inflammatory effect of AR has been attributed to its potent in vitro and in vivo modulating effects on several important cytokines, such as tumor necrosis factor-α (TNF-α)2,22,26,28,31,36,37, interleukin-6 (IL-6)2,26,28,29,31,37, interleukin-1β (IL-1β)2,29,37, and interleukin-10 (IL-10)2,28. Inhibitory effects of AR on the expression levels of other cytokines, such as interleukin-2 and interferon-γ (IFN-γ), were also found in vitro3. Multiple upstream mechanisms for the modulating effect of AR on cytokines were proposed. Both in vivo and in vitro studies showed that AR inactivated NF-kB by inhibiting p65 nuclear translocation, suppressing I-κ phosphorylation2,26,30,37, suppressing phosphorylation of mitogen-activated protein kinases (MAPKs)26,36, and inhibiting phosphorylation of phosphatidylinositide 3-kinases (PI3K) and protein kinase B (AKT)2,26. Other proposed mechanisms include suppression of the Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathway4,29, promotion of degradation of iNOS synthase through the carboxyl terminus of Hsc70-interacting protein (CHIP)-associated proteasome32, and activation of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPKα)37. However, there are few studies on the anti-inflammatory effects of arctiin. In three studies, arctiin was reported to have similar anti-inflammatory effects to those of AR in vitro and in vivo33,38,39.
Effect of AR and arctiin against exogenous pathogens
AR, arctiin, and A lappa also demonstrated inhibitory effects on microorganism (Table 3), including viruses and bacteria, common exogenous stimuli for inflammatory responses. Studies attributed the anti-viral effects of A lappa to the major component AR. AR was reported to have strong anti-viral activities against influenza A in both in vitro and in vivo settings, and the mechanism of the anti-influenza effect of AR was related to the direct inhibitory effect on viral replication5,6,40. Furthermore, protective effects of AR against more lethal pathogens, such as human immunodeficiency virus and Japanese encephalitis virus, were also reported with in vitro and in vivo models7,41,42,43. AR demonstrated inhibitory effects on the bacteria Helicobacter pylori, but this effect was not sufficient to attenuate the gastric carcinogenesis in Mongolian gerbils44. Other anti-bacterial activities of A lappa against pathogens such as Escherichia coli and Pseudomonas aeruginosa were all demonstrated using the extract of the herb on in vitro disk diffusion models45,46,47,48. In addition, inhibitory effects of A lappa on other microorganisms, such as fungi, were also demonstrated46. However, whether these effects are attributed to AR and arctiin is still unclear.
Anti-inflammatory activities of AR and arctiin on chronic diseases
AR and arctiin have also been associated with beneficial effects on some chronic diseases, such as metabolic disorders and central nervous system dysfunctions, partially due to their anti-inflammatory activity. AR and arctiin demonstrated their effects on ameliorating metabolic disorders in various cell lines49,50,51, ob/ob mice, and streptozotoxin (SZT)-induced diabetic rats8,9,10. Neuroprotective effects of AR were demonstrated on cultured neuron cells, cerebral ischemia rats, memory deficit mice, experimental autoimmune encephalomyelitis in mice, Aβ-induced AD mice, and transgenic Alzheimer's disease mice11,12,13,52,53. Multiple mechanisms for these neuroprotective effects were proposed, including scavenging free radicals, down-regulating pro-inflammatory cytokines, regulating AMPK and PPAR-γ/ROR-γt signaling, reducing Tau hyperphosphorylation and inhibiting Aβ production11,12,13,52,53,54. In addition, although AR and A lappa demonstrated their potential anti-cancer activities on various cancer cell lines, there is still a lack of sufficient evidence for their anti-cancer activities on in vivo models21,55,56,57,58,59.
In summary, AR was reported as the most potent bioactive component of A lappa in the majority of studies, while the bioactivities of arctiin were lower than those of AR in most reports evaluating both compounds. AR demonstrated potent effects on inflammatory responses. The anti-inflammatory effect of AR may function synergistically with its anti-viral effect to manage some infectious conditions. However, inflammatory responses also have a role in the progression of several chronic diseases, and AR may serve as an auxiliary treatment for these chronic diseases, including metabolic disorders and central nervous system dysfunctions.
Pharmacokinetic properties of AR and arctiin
Despite the research attention AR has received due to its promising therapeutic potential, biopharmaceutic and pharmacokinetic investigations of AR and arctiin are rare. In this section, we will discuss the pharmacokinetic properties of arctiin and AR, including the absorption, distribution, metabolism and excretion characteristics, focusing on the biotransformation of arctiin and AR. Furthermore, comparison will be made among the pharmacokinetic profiles of AR after various routes of administration.
Pharmacokinetic properties of arctiin
AR was regarded as the only metabolite in most in vivo pharmacokinetic studies of arctiin, due to its much higher concentration in plasma compared with that of arctiin5,60. However, in vitro incubation studies of arctiin or AR with intestinal content or feces revealed that intestinal microbiota mediated the biotransformation of arctiin to AR in the intestine61,62, followed by demethylation and a series of other biotransformation processes leading to the formation of enterolactone (3 ) 63,64,65. Wang et al reported three metabolites in rat urine and feces after oral administration of 30 mg/kg arctiin (1), including AR (2), enterolactone (3) and (2R,3R)-2-(3′-hydroxybenzyl)-3-(3″,4″-dimethoxybenzyl)-butyrolactone, an intermediate metabolite66 (Figure 2).
Pharmacokinetic properties of AR
The pharmacokinetic properties of AR are summarized in Table 4. After oral ingestion, efficient absorption of AR was demonstrated in a Caco-2 cell monolayer transport study and a rat in situ intestinal perfusion model67,68. The duodenum was found to be the best absorption segment of AR among all the intestinal segments67. Although the Caco-2 cell monolayer model showed that no significantly active efflux was involved during the absorption of AR, with an efflux ratio of 1.1768, an in situ intestinal perfusion model showed that absorption of AR in the duodenum was significantly improved by co-treatment with the P-glycoprotein (P-gp) inhibitor verapamil67, suggesting AR is a potential P-gp substrate.
After entering the systemic circulation, AR exhibited a strong binding capacity (99.8%–100%) to plasma. The high plasma binding was found in various species, including human, beagle dog, and rat69. The tissue distribution of AR was only investigated after hypodermic or oral administration to rats. After hypodermic injection of 0.806 μmol/kg AR to rats, the AR concentrations were reduced at 6 h to approximately 1/10 of their peak values at 0.25 h in most organs, indicating no accumulation in tissues, and the peak concentration of AR was in the intestine, followed by the heart, liver, pancreas, and kidney69. After oral administration of 70 mg/kg AR to rats, the tissue concentration of AR peaked at 30 min and was quickly eliminated within 4 h, and the concentration of AR was highest in the spleen, followed by the liver and the other organs70.
AR was eliminated via extensive metabolism to various metabolites. The dominant metabolic pathways of AR are summarized in Figure 2. In vitro incubation of AR with the intestinal microbiota demonstrated that similar to acrtiin, AR can be biotransformed into a series of demethylation and dehydroxylation products, such as 3'-demethylarctigenin, 3'-demethyl-4'-dehydroxyarctigenin, and eventually to the enterolactone (3) anaerobically within 24 h61,65,71. In rats, extensive first-pass metabolism of AR occurred in both the intestine and liver, with the formation of two major in vivo metabolites, namely, arctigenic acid (4) and arctigenin-4'-O-glucuronide (5)68,72,73,74. Further in vitro and clinical studies confirmed that similar biotransformation also occurred in humans. The hydrolysis of AR was mediated by human paraoxonase 1 in plasma73, and glucuronidation of AR was mediated by UGT1A9, UGT2B7 and UGT2B17 in the liver and intestine74. A phase I clinical trial of the herbal product GBS-01 on pancreatic cancer patients demonstrated that after oral administration of GBS-01 at a dose of 12 g AR per person, the area under the plasma concentration versus time curve (AUC) of arctigenin-glucuronide was almost 1000 times higher than that of AR75. Notably, the extent of metabolism of AR might be different between species. As reported by Li et al, approximately 62%, 3.7%, 25.9% and 15.7% of the AR remained after incubation in human, monkey, dog, and rat liver microsomes for 90 min69. Other minor in vivo metabolites found in SD rats include 4-O-demethylarctigenin, arctigenin 4-O'-sulfate, arctigenic acid-4'-O-glucuronide, and 4-O-demethyl-arctigenin-4,4'-O-di-glucuronide72,73. Following rapid formation, fast elimination of the two major metabolites was observed after both intravenous and oral administration of AR to rats. Several glucuronidation products of AR, including arctigenin-4'-O-glucuronide (5), were excreted via bile, with potential enterohepatic circulation suggested72. These complex metabolic pathways of AR were described and verified by an integrated semi-mechanistic pharmacokinetic model of rats72 and warrant further verification in human trials.
Due to the extensive first-pass metabolism of AR, it is likely that most AR, either as single compound or as active component in herbal preparations, would be quickly metabolized after oral administration. As shown in Table 5, after oral administration, the plasma concentrations of AR were very low and even undetectable in various animal models, suggesting poor oral bioavailability. The pharmacokinetic profile of AR in humans after oral administration was investigated in a phase I clinical trial of the herbal product GBS-01. After oral administration of GBS-01 at a dose of 12 g AR per person, the peak concentration of AR in the plasma of the pancreatic cancer patients was 66.56±26.81 ng/mL, and the AUC was 487.97±368.86 ng*h/mL75. Given the low molecular weight of AR and its high permeability demonstrated in the absorption models, the poor oral bioavailability of AR should be mainly due to its extensive first-pass metabolism rather than limitations of membrane permeability. Thus, delivering AR through alternative administration routes might be plausible to bypass the first-pass metabolism and improve its bioactivities. Alternative routes for administration of AR, including hypodermic injection and sublingual administration, were tested on experimental animals. The results demonstrated substantially improved AUC and bioavailability of AR after hypodermic or sublingual administration compared with that from the oral administration (Table 5)69. These results suggested that optimization of the administration routes for AR may potentially improve its therapeutic efficacy by increasing the systemic and target organ exposure. Further pharmacokinetic/pharmacodynamic studies of AR after different routes of administration are warranted.
As described previously, AR and arctiin served as marker compounds in the quality control of numerous proprietary Chinese medicines. Most of these products are for treatment of common cold, flu and related symptoms, such as various dosage forms of Yinqiaojiedu decoction76,77,78, Lingyang ganmao decoction79,80 and Fengreganmao granules81,82. Despite its popularity, Fructus Arctii is not commonly used alone. Therefore, reports on the clinical trials of AR, arctiin or A lappa alone are rather limited. As summarized in Table 6, only four clinical trials were identified for evaluation of the therapeutic effects of AR, arctiin or A lappa, with diverse indications. Despite their high Jadad scores (2 out of 3 received full score of 5)83, three randomized controlled trials demonstrating the efficacy of arctiin (0.5–1 g, t.i.d.) or Fructus Arctii (20 g, t.i.d.) against diabetic nephropathy were actually reported by the same group, with a similar study design and dose regiments84,85,86. A recent phase I clinical study co-sponsored by the Japanese National Institute for Cancer Research and Kracie Pharmaceutical Co, Ltd confirmed the safety of an oral product containing a high content of AR (GBS-01) (dose equal to 3 to 12 g daily)75. Moreover, a study protocol for evaluating A lappa-containing moisturizing cream for dry skin and itch relief in a randomized, double-blind, placebo-controlled trial was published87. Similarly, A lappa was also demonstrated to effectively treat acne vulgaris in a recent uncontrolled observational interventional study in India88. The anti-inflammatory effects of AR, arctiin or A lappa have not yet been confirmed in the clinic. Further randomized controlled trials are needed to evaluate the therapeutic efficacy of AR and arctiin.
Inflammatory responses are an important part of various acute and chronic disease conditions. AR, as the most potent bioactive component of A lappa with anti-inflammatory activities, is a promising therapeutic compound against acute inflammation as well as several chronic diseases. However, pharmacokinetic investigations suggested that the extensive first-pass metabolism of AR would hinder its in vivo and clinical efficacy after oral administration. To optimize the in vivo and clinical efficacy of AR, alternative administration routes other than oral administration are suggested. AR could be delivered through sublingual or buccal routes that allow rapid onset of the treatment of acute inflammation and influenza; transdermal routes for the treatment of skin conditions; and the intranasal route for targeting central nervous system dysfunctions. In addition, considering the extensive first-pass metabolism of AR and the higher plasma concentrations of metabolites compared with parent compound observed, the potential pharmacological effects of the metabolites of AR should be studied. Further reports with simultaneous monitoring of pharmacokinetics and pharmacological properties are essential for a better understanding of the effects of AR.
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This work is supported by Direct Grant 3800005 from the Chinese University of Hong Kong and research fund 7010213 from the Health Authority of Hong Kong, China.
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Gao, Q., Yang, M. & Zuo, Z. Overview of the anti-inflammatory effects, pharmacokinetic properties and clinical efficacies of arctigenin and arctiin from Arctium lappa L. Acta Pharmacol Sin 39, 787–801 (2018). https://doi.org/10.1038/aps.2018.32
- Arctium lappa L
- Fructus Arctii
- anti-inflammatory agents
- clinical efficacy
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