Impact of Traditional Chinese Medicine Antioxidants on Oxidative Stress and Drug-Induced Liver Injury: A Review

Introduction

In recent years, drug-induced liver injury (DILI), as an important clinical problem, has attracted widespread attention and research. DILI encompasses hepatic dysfunction attributable to pharmaceutical agents, herbal remedies, nutritional and dietary supplements, and healthcare products, including their reactive metabolites and excipients, as well as associated pollutants and impurities. This condition manifests clinically through abnormal liver function, hepatocyte necrosis, and liver fibrosis, and potentially progresses to liver failure [1,2]. DILI is very common, and its incidence has gradually increased with the continuous development and use of new drugs [3,4]. Currently, there is a lack of effective drugs to treat DILI. Therefore, it is important to study the repair and prevention of DILI [5].

Oxidative stress, as an important pathophysiological process [6–8], plays a vital role in the occurrence and development of DILI. An imbalance of oxidants and antioxidants in the body will lead to excessive reactive oxygen species (ROS) and free radicals, which trigger an oxidative stress response and damage the structure and function of liver cells [9,10]. Reports showed that mitochondria, especially via NADPH oxidase (NOX), are the most important sites of ROS formation in the cell [11,12]. Antioxidants in Traditional Chinese Medicine (TCM) comprise natural compounds with free radical- and ROS-scavenging abilities [13–16], which have been widely studied for their potential to repair DILI [17–19]. Antioxidants are prevalent in TCM and can be categorized into various types according to their natural chemical structures [20]. Although TCM sources include plants, animals, and minerals, the primary origin of antioxidants is medicinal plants. Therefore, the TCM antioxidants examined in this article predominantly derive from medicinal plants.

The liver serves as the principal organ for detoxification and possesses a robust regenerative capacity following injury [21,22], enabling substantial functional recovery under suitable conditions. Furthermore, its highly active metabolic processes result in the generation of ROS within its cells. Drug-induced hepatotoxicity further amplifies ROS production, culminating in pronounced oxidative damage [23]. Consequently, the prompt elimination of excessive ROS is imperative to mitigate oxidative damage and expedite the repair of compromised hepatic cells. Medicinal plants are rich sources of antioxidants, particularly polyphenols, which play a crucial role in the repair of damaged liver cells [24]. Previous reviews have predominantly focused on the general protective effects of medicinal plants used in TCM on DILI [25]. However, there is a paucity of specialized summaries addressing the auxiliary repair effects and underlying mechanisms of antioxidants in TCM treatments on DILI.

The present review aims to comprehensively analyze the repair mechanisms of antioxidants (especially phenolics) in TCM to alleviate DILI caused by ROS. These antioxidants exert their function by decreasing ROS accumulation, increasing antioxidant enzyme activities, restoring the redox balance, reducing the inflammatory response of hepatocytes, and promoting hepatocyte regeneration [8,25–28]. Furthermore, antioxidants in TCM also show a synergistic effect in that they enhance scavenging of ROS and free radicals [29]. It has been suggested that antioxidants in TCM have significant potential to repair DILI [30–32]. In comparison with modern medicine, which typically utilizes single-ingredient drugs, TCM comprises multiple active ingredients, alongside various other components such as antioxidants and numerous currently unidentified compounds [25]. The unidentified constituents and mechanisms of action of plant-based drugs derived from TCM may contribute to their potential to repair DILI.

Here, we performed an extensive search using Google Scholar and the PubMed search engine. We mainly limited our review to human and animal studies in DILI research. In addition, only papers written in English were included.

In this article, we aim to review the role of antioxidants in TCM and their effects on DILI.

ROS, Free Radicals, and Human Health

Aerobic organisms produce ROS, including superoxide anions and hydrogen peroxide, as well as free radicals like hydroxyl radicals, during metabolic processes such as respiration, due to the partial reduction of oxygen [6,33]. When these small molecules are generated and accumulate in substantial amounts, they can induce oxidative damage to cellular macromolecules, including lipids, proteins, and nucleic acids, owing to their potent oxidizing properties. This oxidative stress can subsequently disrupt normal cellular metabolism [6,34]. While elevated levels of ROS and free radicals are detrimental to organisms, low concentrations of ROS serve as signaling molecules [34]. To maintain ROS and free radicals within a low concentration range, the antioxidant system is activated, comprising both enzymatic and non-enzymatic antioxidants [6,34]. In animal cells, enzymatic antioxidants primarily include superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Non-enzymatic antioxidants produced in animal cells predominantly include glutathione and uric acid, among others. Additionally, there are non-enzymatic antioxidants such as ascorbic acid, vitamin E, and polyphenols, which cannot be synthesized endogenously by animal cells and must be acquired through dietary intake [6,35]. Excessive accumulation of ROS and free radicals, coupled with inadequate clearance, can result in oxidative stress and disruption of redox homeostasis, thereby contributing to metabolic disorders. This imbalance may exacerbate the severity of these conditions and potentially precipitate the onset of chronic and degenerative diseases [7,36]. For instance, the processes of aging and inflammation in human skin are intricately linked to ROS [37]. Furthermore, oxidative stress plays a crucial role in the pathogenesis of drug-induced hepatitis, with antioxidant therapy serving as an effective intervention to mitigate its severity [38].

Antioxidant Intake and Human Health

In comparison with the antioxidants present in animal cells, plants exhibit a greater diversity and abundance of antioxidants, particularly non-enzymatic antioxidants such as vitamin C and polyphenols. This phenomenon may be attributed to the autotrophic nature of plants and their immobility, necessitating the synthesis of a higher quantity of antioxidant metabolites to mitigate ROS toxicity induced by environmental stressors [39]. Numerous human diseases are associated with the failure to efficiently eliminate ROS, resulting in oxidative stress and redox imbalance [40,41]. To mitigate the detrimental effects of associated diseases, it is imperative for humans to acquire antioxidant nutrients from plant sources to more efficiently counteract the accumulation of ROS and free radicals within cells [42–44]. In everyday life, individuals obtain antioxidants, including vitamin C and polyphenols, through the consumption of fruits and vegetables, thereby promoting physical health [45]. This concept is encapsulated in the adage, “An apple a day keeps the doctor away.” This statement indicates that apples are abundant in antioxidants, including vitamin C and polyphenols, which contribute significantly to human health maintenance [46]. Nonetheless, depending exclusively on antioxidant metabolites from fruits and vegetables is insufficient for restoring patients’ health. Prior to the advent of modern medicine, traditional medicine frequently utilized plant-based remedies to treat various diseases, which also contained substantial quantities of antioxidant metabolites [47]. Plant-based pharmaceuticals are characterized by the presence of specific metabolites with therapeutic potential [48], as well as a substantial concentration of antioxidants, which may have significant biological roles. Consequently, these antioxidants represent a vital source for acquiring plant-derived antioxidants beyond those found in fruits and vegetables [47,49].

Pathogenesis and Treatment of DILI

DILI refers to a disease that causes abnormality or damage to liver function because of the direct or indirect action of drugs, which can be broadly divided into 2 categories [50–52]. In the first category, the drug has a direct toxic effect on liver cells, leading to liver cell damage and death. In the second category, the drug causes an immune response through metabolites produced by its degradation, leading to hepatitis or cholestatic liver disease [50]. The clinical characteristics of DILI comprise abnormal liver function, elevated liver enzymes, and jaundice. Severe DILI can also lead to liver failure [1,2]. In addition, DILI has the following characteristics [51,53]: First, DILI is dose-dependent, ie, the greater the drug dose, the higher the risk of liver injury. Second, there are differences in the toxic effects of different drugs on the liver. Some drugs have direct toxic effects, while other drugs cause an immune response through metabolites produced by drug degradation [38], resulting in liver damage. In addition, individual differences are also an important factor in DILI [54], such as the differences in the sensitivity of different individuals to drugs, and the fact that some people might be more likely to experience liver damage in response to a certain drug.

At present, the approaches and strategies for managing DILI can be delineated as follows [55]: First, it is essential to discontinue the medication responsible for the DILI. Second, pharmacological interventions may include the administration of hepatoprotective agents (eg, glutathione), anticholestatic medications (eg, cholestyramine), immunosuppressants (eg, glucocorticoids), and other therapeutic agents. Third, non-pharmacological interventions such as liver transplantation and artificial extracorporeal liver support may be considered. It is noteworthy that the management of DILI resulting from drug misuse or inappropriate use, particularly with contemporary chemical pharmaceuticals, frequently entails the administration of protective agents alongside drug cessation. Antioxidants are commonly incorporated within these protective agents [55]. Nonetheless, the application of certain synthetically derived antioxidant protectants, such as N-acetylcysteine, is contraindicated in pediatric patients under the age of 2 years [56]. Furthermore, elevated concentrations of antioxidants employed in the treatment of liver diseases may induce adverse effects, including pro-oxidant activity, reduction in glutathione-S-transferase enzyme activity, inhibition of detoxification processes, and interference with coagulation [57]. While the misuse of plant-based medications from TCM can also result in DILI, such occurrences are considerably less frequent in comparison with those associated with Western pharmaceuticals [58]. This suggests that artificially synthesized pharmaceuticals, including those employed as antioxidant protectants, exhibit certain limitations and deficiencies. In contrast, traditional medical approaches to the treatment of DILI frequently achieve favorable therapeutic outcomes with reduced adverse effects through the use of appropriately selected plant-based medications. This efficacy may be attributed to the abundant antioxidants inherently present in plant-derived drugs [40].

Oxidative Stress and DILI

Studies have found that the pathophysiological process of DILI is closely related to oxidative stress [1,38,52,59,60]. Moreover, one commonly accepted mechanism of DILI is the transformation of a nontoxic parent drug into a chemically reactive metabolite and the accumulation of ROS and free radicals [38,52], which can trigger hepatitis through direct toxicity or immune reactions [3,61]. Research has shown that mitochondria are the most important sites of ROS formation in the cell [12]. Drugs that cause liver injury often directly disrupt mitochondria to cause stress in hepatocytes [61–63]. However, phenolics can repair DILI by attenuating oxidative damage and decreasing mitochondrial dysfunction [64–66]. Similarly, NOX is a key enzyme for ROS production and is closely related to liver disease [11,67,68]. For example, a study reported that rosiglitazone can alleviate acetaminophen-induced acute liver injury by downregulating hepatic NOX activity [69]. Interestingly, NOX can also be markedly inhibited by phenolics in animal cells [70].

The ROS and free radicals produced in this process will cause oxidative damage to biological molecules (Figure 1), such as cell membrane lipids, proteins, and nucleic acids, resulting in abnormal liver cell function [9,10]. Reports have shown that oxidative stress can lead to the depletion of antioxidants (eg, glutathione) in liver cells [32,71]. Therefore, the pathophysiological process of DILI is closely related to the lack of sufficient antioxidants in liver cells.

Antioxidants can remove ROS and free radicals from the body, reduce oxidative stress, and protect liver cells from oxidative damage [6,72]. Studies have shown that some plant active ingredients in TCM have strong antioxidant activity and can repair DILI [17,18,25,30–32]. However, further in-depth research is needed. The study of antioxidants in TCM could provide new ideas and methods to treat DILI. Therefore, the antioxidants in TCM have important research value for the repair of DILI.

Antioxidants Are Widely Found in TCM

Despite the rapid development of modern medicine, the search for new therapeutic agents to treat DILI is still ongoing. Many synthetic drugs have demonstrated strong ROS and free radical-scavenging abilities; however, they almost always cause liver damage [3,73].

However, TCM represents a large resource for modern medicine [74]. Recently, studies have revealed the possible mechanisms of action of natural products at different levels. Some natural products derived from TCM (eg, silymarin, resveratrol, curcumin, and gingko) have been extensively investigated for their ability to alleviate DILI, their lower toxicity, their high efficacy, and their wide availability [32,75,76].

Compared with modern Western medicine, TCM refers to the holistic approach to diagnosis, pathophysiology, and therapy in the Chinese materia medica, based on over 2000 years of accumulated knowledge and practice [77]. Although Chinese herbal medicine abuse can induce DILI, it has still been used widely for thousands of years [78–80]. Medicinal plants are an essential part of TCM [81] and Chinese herbal medicines comprise more than 1500 medicinal plants and many composite preparations [13].

TCM is a traditional drug resource in China, a resource that includes many antioxidants [13,16]; compounds or substances with ROS- and free radical-scavenging capacities. The ROS and free radical defense mechanism consists of antioxidant machinery (enzymatic and non-enzymatic antioxidants), which helps to mitigate oxidative stress-induced damage [6,8]. Based on the similarities and differences in their chemical structures and formulas, these plant secondary metabolites with ROS and free radical-scavenging abilities can be classified into different types [20]. Plant secondary metabolites (such as polyphenols and flavonoids) are widely used in medicine, especially to treat DILI (Figure 2).

As shown in Figure 2, the most well-known antioxidants among plant secondary metabolites are polyphenols [13]. Polyphenols have strong free radical-scavenging ability and antioxidant activity, and are widely distributed in TCM [82]. In addition, other types of secondary compounds, such as flavonoids, saponins, terpene, alkaloids, and glycosides all have strong ROS and free radical-scavenging capacities and have been used frequently to treat DILI [83–89]. These substances can be divided into many types and are widely distributed in different TCMs [13,16]. Some natural products containing polyphenols are considered as potential chemopreventive and hepatoprotective agents (Table 1).

In addition, antioxidants, such as ascorbic acid, glutathione, carotenoids, and some peptides with antioxidant activity, are also found widely in fresh TCM preparations [90]. These substances can exert an antioxidant function through different channels and play a certain role in the repair of DILI. The synergistic effect between antioxidants means that consuming multiple fruits, vegetables, or tea at the same time is more beneficial for physical health than consuming them singly [91,92]. Similarly, the synergistic effects of Chinese herbal medicine to enhance ROS and free radical scavenging have also been reported [92,93]. For example, the combination of some phenolics and flavonoids had synergistic effects on free radical scavenging [94].

Repair Mechanism of DILI by Antioxidants in TCM

As an important drug resource, TCM has a long history and wide application [95,96]. In recent years, increasing numbers of laboratory and clinical studies have shown that antioxidants in TCMs play an important role in the repair of DILI (Table 2) [18,25,32]. Interestingly, all these antioxidants extracted from TCM could alleviate DILI by enhancing antioxidant enzyme activities in rat liver tissues (Table 2; [97–100]).

Cell oxidative damage is an important factor leading to the occurrence and development of many diseases [8]. In recent years, studies have shown that antioxidants in TCM have the potential to repair cellular oxidative damage. For example, Panax ginseng mainly comprises ginseng saponins. A study found that ginseng has significant antioxidant activity and can inhibit the oxidative stress response of the liver and reduce the hepatocyte damage caused by DILI [101].

Antioxidants can reduce oxidative damage by directly removing free radicals [8]. Free radicals are the main product of oxidative reactions, which can cause oxidative damage to biological macromolecules (such as lipids, proteins, and nucleic acids) in cells. Antioxidants have the ability to capture free radicals, thus reducing the occurrence of oxidation reactions and protecting cells from oxidative damage [6,9,10]. Several studies have shown that antioxidants in TCM can reduce DILI by inhibiting oxidative stress and reducing the production of free radicals [100,104]. For example, in vitro, flavonoids in Scutellaria baicalensis Georgi showed significant antioxidant activity, which could reduce drug-induced oxidative damage to hepatocytes [105]. Some polyphenols extracted from plants [98,99,106], such as gallic acid [107], curcumin [108,109], and resveratrol [110], can remove the free radicals in liver cells caused by drug-induced hepatitis, restore oxygen balance, regulate antioxidant enzymes, and repair oxidative damage.

Antioxidants can also repair oxidative damage by regulating intracellular redox balance [27,111]. Redox balance is one of the important factors that maintain the normal function of cells. During cell oxidation injury, the production of oxidants destroys intracellular redox balance, leading to abnormal cell function. Antioxidants can repair oxidative damage by increasing the level of reducing agents or reducing the level of oxidants, thus restoring the intracellular redox balance [27].

Antioxidants can also repair oxidative damage by regulating the activity of intracellular antioxidant enzymes [6,97]. Antioxidant enzymes are an important antioxidant defense system in cells, which can convert oxidants into harmless substances and reduce the occurrence of oxidation reactions. However, antioxidant enzymes can be inactivated by free radicals and oxidative stress [112,113]. Interestingly, it was found that antioxidants can enhance intracellular antioxidant ability by regulating the activity of antioxidant enzymes, thus repairing oxidative damage (Table 2). For example, CCl4-inhibited antioxidant enzyme activities (eg, from superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase) could be markedly reversed using an extract of the herb Euphorbia dracunculoides in rat liver tissues [97].

Antioxidants can also repair oxidative damage by inhibiting inflammatory reactions [26,114–116]. Oxidative damage is closely related to inflammatory reactions. The accumulation of oxidants will trigger inflammatory reactions and further aggravate cell oxidative damage. Antioxidants have an antiinflammatory effect, which can inhibit the occurrence of inflammatory reactions and reduce cell oxidative damage. These antioxidants can also regulate the activation of inflammatory signaling pathways, promote the removal of inflammatory factors to decrease inflammatory reactions, and accelerate the repair of DILI. For example, in bile duct ligated rats, the levels of serum proinflammatory cytokines (TNFα, IL-1β, and IL-6) were decreased by swertiamarin, an herbal agent derived from Swertia mussotii Franch, which can alleviate liver injury [114].

Antioxidants in TCMs can also promote DILI repair by regulating apoptosis and regeneration in liver cells [28,117]. A study found that antioxidants in some TCMs can inhibit druginduced apoptosis and reduce cell death, thus protecting the liver from damage [28]. For example, Astragalus (Astragalus membranaceus Fisch) Bunge is a TCM that is widely used in clinical practice. Its main components are flavonoids. Astragalus has obvious antioxidant activity and can reduce the oxidative stress response of the liver caused by DILI, and promote the repair and regeneration of liver cells [118]. In addition, Lycium chinense Miller (producing wolfberries) is also a commonly used Chinese medicine. Its main ingredient is Lycium polysaccharide. Wolfberry polysaccharides have antioxidant activity that can reduce the oxidative stress response of hepatocytes caused by DILI and promote the repair and regeneration of hepatocytes [102].

TCM contains a large number of plant-derived drugs, and the antioxidants they contain can also repair cell oxidative damage through a variety of mechanisms (Figure 3) [15,16], with broad application prospects. In addition, many plant extracts from TCM have been reported to repair DILI via their antioxidants [103,119,120].

Future Directions

Despite advancements in research on antioxidants in TCM for the treatment of DILI, several limitations persist. These include the paucity of large sample sizes, the absence of multi-center clinical trials, and insufficient in-depth investigations into the underlying mechanisms. Furthermore, challenges remain in the application of antioxidants from TCM in the treatment of DILI, particularly when considering the use of medicinal plants.

Firstly, the identification of active ingredients and the reduction of hazardous substances are paramount [80]. TCM not only encompasses a rich array of antioxidants but also includes various other components with pharmacological effects that remain unclear [121]. This complex mixture poses challenges for precise disease treatment, necessitating further identification of unknown metabolites and the minimization of their potential negative effects. Furthermore, the intensification of environmental pollution has led to an increase in toxicity due to heavy metals in medicinal plants [122]. If these toxicities are not effectively controlled within a safe range, they may introduce new hazards.

Secondly, the advancement of cultivation techniques for medicinal plants is essential to enhance the concentration of antioxidants. While medicinal plants sourced from the wild exhibit higher levels of antioxidants, their availability is limited and their extraction can potentially harm the ecological environment. Conversely, although artificially cultivated medicinal plants exhibit rapid growth, their antioxidant content is frequently significantly lower compared with their wild counterparts [123]. Consequently, it is imperative to develop innovative technologies aimed at augmenting the antioxidant content in cultivated medicinal plants.

Thirdly, consistent analysis and content labeling of antioxidants in medicinal plants is crucial. Given that TCM predominantly utilizes cultivated medicinal plants, the antioxidant content in these cultivated varieties is frequently lower than that found in their wild counterparts [123]. Consequently, it is imperative to perform labeling of the antioxidant ingredients from various parts of the same batch of cultivated medicinal plants (eg, roots, leaves, fruits, seeds) to ensure adequate dosage and to achieve the desired therapeutic outcomes.

Fourthly, the investigation into the synergistic mechanisms of antioxidants within TCM necessitates elucidation. Understanding the interactions among various antioxidant compounds in TCM that synergistically enhance the mitigation of DILI demands the application of advanced technologies, such as multi-omics approaches, to reveal the underlying regulatory mechanisms [124].

Finally, research efforts are focused on mitigating the presence of harmful components in medicinal plants. The improper use of plant-based drugs can result in DILI. Consequently, it is imperative to explore strategies for reducing harmful constituents in the secondary metabolite synthesis of various medicinal plants [80].

The aforementioned shortcomings represent critical areas requiring enhancement of and focused attention on the future application of antioxidants in TCM for the treatment of DILI. Furthermore, it is imperative to intensify future research efforts to optimize the use of TCM in DILI treatment. This research should encompass several key aspects:

First, integrating multiple omics techniques could elucidate the repair mechanisms of DILI mediated by antioxidants in TCM, thereby providing a theoretical foundation for the development of novel antioxidant therapeutic agents.

Second, clinical trials are needed to assess the therapeutic efficacy of antioxidant compounds in TCM for the treatment of DILI.

Third, fundamental research to identify additional TCMs with antioxidant properties needs to be undertaken, thereby expanding the therapeutic options for DILI management.

Finally, advanced technologies need to be developed to enhance the concentration of active ingredients, including antioxidants, in cultivated TCM plants, and to eliminate harmful substances from these plants.

Despite existing limitations, ongoing research and clinical trials are expected to substantiate the role of these antioxidants as a pivotal strategy in DILI treatment. This advancement is anticipated to enhance therapeutic outcomes and improve the quality of life for patients, particularly in developing countries and economically disadvantaged regions.

Conclusions

The inappropriate administration of pharmaceuticals can result in a substantial accumulation of ROS and free radicals, thereby inducing oxidative stress and aggravating hepatic injury. The application of various phytotherapeutic agents derived from TCM has demonstrated efficacy in mitigating DILI. This therapeutic effect is potentially attributable to the presence of specific bioactive compounds that facilitate the repair of damaged hepatocytes, as well as the high concentration of antioxidant metabolites. The mechanisms through which antioxidant metabolites from TCM effectively mitigate DILI have been thoroughly examined, and several commonly utilized medicinal plants for DILI treatment have been systematically reviewed. Furthermore, the limitations and future potential of employing these medicinal plants for DILI management have been analyzed, offering valuable insights for future research endeavors.