Herbal Therapy for the Treatment of Acetaminophen-Associated Liver Injury: Recent Advances and Future Perspectives

Chang, Leslie; Xu, Dongwei; Zhu, Jianjun; Ge, Guangbo; Kong, Xiaoni; Zhou, Ying

doi:10.3389/fphar.2020.00313

Cited by 32 publications

(28 citation statements)

References 104 publications

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“…Accumulating studies have indicated a relationship between the gut microbiota and APAP-induced-liver injury [ 27 , 28 ]. Additionally, recent studies have suggested that traditional Chinese medicine, as effective and potential prebiotics, could modulate the gut microbiome to prevent the development of various diseases [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen‐Induced Liver Injury

Hong

Liu

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Oridonin (OD), which is the major active ingredient of the traditional Chinese medicine Rabdosia rubescens, reportedly exerts anti-inflammatory and antioxidative effects. Here, we first find that OD protects against APAP-induced hepatotoxicity. The results of hepatic tissue-associated RNA-seq and metabolomics showed that the protective effects of OD were dependent upon urea cycle regulation. And such regulation of OD is gut microbiota partly dependent, as demonstrated by fecal microbiota transplantation (FMT). Furthermore, using 16S rRNA sequencing, we determined that OD significantly enriched intestinal Bacteroides vulgatus, which activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to regulate redox homeostasis against APAP by urea cycle. In conclusion, our study suggests that the Bacteroides vulgatus-urea cycle-Nrf2 axis may be a potential target for reducing APAP-induced liver injury, which is altered by OD.

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Section: Discussionmentioning

confidence: 99%

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen‐Induced Liver Injury

Hong

Liu

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Therefore, many countries spend tremendous efforts developing drugs based on the medicinal properties of plants which are thought to be safer than chemically designed drugs. More specifically, the Chinese natural products industry focused on identifying plant extracts with beneficial effects against APAP hepatotoxicity [7,8]. For instance, many extracts tested against APAP toxicity in the herbal product field claim to protect via CYP2E1 inhibition.…”

Section: Medicinal Plant Extracts As Therapeutics Against Apap Overdosementioning

confidence: 99%

“…Based on the lack of mechanistic understanding in these studies, it appears that targeting GSH synthesis with natural herbal extracts is not a productive endeavor and it is unnecessary to develop a drug to compete with NAC since it is very efficient at replenishing GSH in humans [4]. From the perspective of interrupting oxidative stress and targeting the Nrf2/Keap1 pathway, an increasing number of herbal extracts studies claim to enhance antioxidant properties that protect against APAP overdose by inducing the Nrf2/Keap1/ARE antioxidant response [8,94].…”

Section: Medicinal Plant Extracts As Therapeutics Against Apap Overdosementioning

confidence: 99%

“…Interestingly, recently published literature indicates that medicinal plants have become a major source in drug discovery efforts against APAP hepatotoxicity because of their chemical diversity as well as biological and therapeutic properties [7]. Indeed, a high number of studies published by the natural products field are focusing on identifying compounds that show a protective effect against APAP overdose [7,8]. However, the molecular mechanism of action of the specific active chemical compounds in these herbal extracts are usually difficult to identify [9], but a number of common therapeutic targets seem to emerge.…”

Section: Introductionmentioning

confidence: 99%

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Novel strategies for the treatment of acetaminophen hepatotoxicity

Akakpo

Ramachandran

Jaeschke

2020

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Despite extensive investigations into the mechanisms of cell death, only a single antidote, N-acetylcysteine, is in clinical use. However, there have recently been more efforts made to translate mechanistic insight into identification of therapeutic targets and potential new drugs for this indication.Areas covered: After a short review of the key events in the pathophysiology of APAP-induced liver injury and recovery, the pros and cons of targeting individual steps in the pathophysiology as therapeutic targets are discussed. While the re-purposed drug fomepizole (4-methylpyrazole) and the new entity calmangafodipir are most advanced based on the understanding of their mechanism of action, several herbal medicine extracts and their individual components are also considered.Expert opinion: Fomepizole (4-methylpyrazole) is safe and has shown efficacy in preclinical models, human hepatocytes and in volunteers against APAP overdose. The safety of calmangafodipir in APAP overdose patients was shown but it lacks solid preclinical efficacy studies. Both drugs require a controlled phase III trial to achieve regulatory approval. All studies of herbal medicine extracts and components suffer from poor experimental design, which questions their clinical utility at this point.

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“…Acetaminophen (APAP) is a representative hepatotoxic drug accounting for most cases of DILI in the United States (Chao et al, 2018). When administered orally, it mainly undergoes two ways of metabolism: (a) sulfonated or glucuronidated by phase II enzymes and (b) first converted into the hepatotoxic N-acetyl-pbenzoquinone imine (NAPQI) by CYPs and then conjugated with glutathione (GSH) (Chang et al, 2020c). Both ways of metabolism function as detoxification and thus any factor that influences them could have an impact on APAP-related hepatotoxicity.…”

Section: Acetaminophenmentioning

confidence: 99%

Connecting the dots: targeting gut microbiota in drug toxicity

Luo¹,

Zhou²

2020

Preprint

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Gut microbiota has been demonstrated to have a vast influence on human health in recent decades and its role in initiating, aggravating, or ameliorating diseases is emerging. Therapeutic strategies have therefore increasingly developed by targeting gut microbial modulation. Recently, its contribution to heterogeneous toxicological responses is also gaining attention, especially in drug-induced toxicity. Oral drugs interact directly with gut microbiota within the gastrointestinal tract and a number of them elicit toxicity mediated by intestinal microbiota. Present studies focus more on the unidirectional influence of how xenobiotics disturb intestinal microbial composition and function and consequently induce altered homeostasis. However, interactions between gut microbiota and xenobiotics are bidirectional and the impact of gut microbiota on xenobiotics especially on drugs should not be neglected. Thus, in this review, we intend to focus on how gut microbiota modulates drug toxicity by highlighting gut microbiota, microbial enzyme, and metabolites to proffer references for seeking common countermeasures in coping with drug toxicity by targeting gut microbiota. Moreover, we give a hypothesis that drugs capable of inducing gut dysbiosis tend to more or less impact the gut-connected organs as evidenced by the drug-induced hepatic encephalopathy, indicating an underlying link among the gut, liver, brain, and other possible organs in drug-induced toxicity.

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Herbal Therapy for the Treatment of Acetaminophen-Associated Liver Injury: Recent Advances and Future Perspectives

Cited by 32 publications

References 104 publications

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen‐Induced Liver Injury

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen‐Induced Liver Injury

Novel strategies for the treatment of acetaminophen hepatotoxicity

Connecting the dots: targeting gut microbiota in drug toxicity

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