Therapeutic potential of bicyclol in liver diseases: Lessons from a synthetic drug based on herbal derivative in traditional Chinese medicine

Highlights

• Bicyclol has therapeutic potential in various pathological conditions in liver.

• Bicyclol has a wide spectrum of pharmacological properties.

• Further studies are required to delineate molecular mechanisms and targets of bicyclol.

• Bicyclol-based therapeutics might be broadly used in clinical practice worldwide.

Abstract

Bicyclol, an innovative chemical drug with proprietary intellectual property rights in China, is based on derivative of traditional Chinese medicine (TCM) Schisandra chinensis (Wuweizi) of North. Mounting data has proved that bicyclol has therapeutic potential in various pathological conditions in liver. In this narrative review, we provide the first summary of pharmacological activities, pharmacokinetic characteristics and toxicity of bicyclol, and discuss future research perspectives. Our results imply that bicyclol has a wide spectrum of pharmacological properties, including anti-viral, anti-inflammatory, immuno-regulatory, anti-oxidative, antisteatotic, anti-fibrotic, antitumor, cell death regulatory effects and modulation of heat shock proteins. Pharmacokinetic studies have indicated that bicyclol is the main substrate of CYP3A/2E1. Additionally, no obvious drug interactions have been found when bicyclol is administered simultaneously with other prescriptions. Furthermore, the results of chronic toxicity have strongly addressed that bicyclol has no noticeable toxic effects on all biochemical indices and pathological examinations of the main organs. In view of good pharmacological actions and safety, bicyclol is anticipated to be a potential candidate for various liver diseases, including acute liver injury, fulminant hepatitis, non-alcoholic fatty liver disease, fibrosis and hepatocellular carcinoma. Further studies are therefore required to delineate its molecular mechanisms and targets to confer this well-designed drug a far greater potency. We hope that bicyclol-based therapeutics for liver diseases might be broadly used in clinical practice worldwide.

Introduction

The liver plays a pivotal role in maintaining metabolic homeostasis and excretion of toxically exogenous and endogenous metabolites associated with drugs, virus and fungus infection, alcoholism and different noxious substances [1]. Given the importance of hepatic function, liver impairment can result in the development of a myriad of pathological and clinical states such as inflammation, liver steatosis, fibrosis and eventually malignancy. Despite a number of conventional medications have been used for treating liver dysfunction, their application are markedly hindered due to poor therapeutic response, intolerance to prescription and unanticipated side effects such as renal and cardiac toxicity in the clinical setting. Therefore these limitations arouse scientific endeavor for searching alternative substitutes among the traditional Chinese medicine (TCM). These Chinese medicinal herbals have existed for a long time and been identified useful in the management of liver diseases, wherein Schisandra chinensis (Wuweizi) of North is one of the effective medicinal herbs that are widely used in liver diseases [2].

It has been evident that Schisandra chinensis and its extracting lignan, that is schizandrin C, represent protective action against liver damage in carbon tetrachloride (CCl₄)-intoxicated mice. Moreover, a novel synthetic drug bicyclol (4,4′ -dimethoxy-5,6,5′,6′-bis(methylene-dioxy)-2-hydroxymethyl-2′-methoxycarbonyl biphenyl) based on schizandrin C is found to exhibit the most effectively pharmacological activity and bioavailability with rare side effects in both basic research and clinical application (Fig. 1a). It was then approved as a hepatoprotectant by the Chinese Food and Drug Administration (CDFA) in 2004 [3]. Bicyclol has been shown to have multiple pharmacological effects including anti-hepatitis virus replication, anti-fibrosis, anti-liver damage and stimulation of hepatocellular protein synthesis in vivo and in vitro [3], [4], [5], [6], [7], [8]. Furthermore, the pharmacological properties of bicyclol have also been explored in areas such as lipopolysaccharide (LPS)-induced acute lung injury, ischemia–reperfusion injury (IRI), neuroprotection, renal carcinoma, idiopathic pulmonary fibrosis as well as hepatic protection (Fig. 1b) [9], [10], [11], [12], [13], [14].

Despite numerous medicinal applications that have been documented for bicyclol through a large number of investigations, there is only one review that provides information with a well-organized collation of the pharmacological effects of bicyclol [3]. However, the latter was published over one decade ago, thus more comprehensive summary of bicyclol is needed due to active exploration of its pharmacological action and in-depth molecular mechanisms. Keep this in mind, we searched for studies on the therapeutic effect of bicyclol in liver diseases. Additionally, we arranged these results according to the critical activities that occur during the pathogenic stages from liver dysfunction to hepatocarcinogenesis.