Herbs to Treat Drug-Induced Liver Injury

Recent research on the hepatorestorative and hepatoprotective properties of active ingredients in traditional Chinese medicine

Active ingredients in herbs from traditional Chinese medicine have shown promising efficacy in rehabilitating and protecting the liver after injury from excess acetaminophen. 

Drug-induced liver injury
A significant number of cases of acute liver failure are caused by acetaminophen, also known as paracetamol. Acetaminophen is not toxic to the liver, but its reactive metabolite may cause liver injury. Excess quantities of acetaminophen can deplete the glutathione needed to convert the toxic metabolite NAPQI into a nontoxic metabolic product. Toxins generated during metabolization, mitochondrial dysfunction, inflammatory response, oxidative stress, the release of damage-associated molecular patterns (DAMPs), autophagy, endoplasmic reticulum stress, and microcirculatory dysfunction are among the mechanisms of injury.
 
Limits of pharmacologic drugs 
The chief pharmacologic agent used for the clinical treatment of acetaminophen-induced liver injury is N-acetylcysteine (NAC), but NAC has limited treatment results and its administration is time-sensitive. For optimal results, NAC is administered approximately one hour after oral acetaminophen.
 
Protective effects of traditional Chinese medicine
A number of active ingredients discovered in Chinese herbs suppress liver toxicity. These compounds vary in how they benefit liver injury: they may alleviate liver disease, mitigate damage to liver tissue, reduce the degree of liver injury, and prevent or ameliorate side effects by suppressing the pathways and mechanisms of liver injury. These active ingredients are fast acting, with notable efficacy and few toxic side effects, and include polyphenol compounds, flavonoid compounds, saponins, organic acids, terpenoid compounds, phenylpropanoids, polysaccharides, and alkaloids. 

Mangosteen pericarp, a source of α-mangostin

Schisandra fruit

Polyphenol compounds
Polyphenol compounds are widely present in traditional Chinese herbal remedies. Polyphenols  can affect the production of biomarkers associated with oxidative stress, a major cause of hepatotoxicity induced by acetaminophen overdose. In the research of Hasanein (2017), rosmarinic acid (found in basil, rosemary, and lemon balm) produced remarkable hepatoprotective effects by inhibiting CYP2E1 activity in the liver and lipid peroxidation.
 
Flavonoid compounds 
The protective effects of flavonoid compounds include the effects of ginseng anthocyanins on acetaminophen-induced hepatotoxicity (Qi 2017) and hyperoside which can hinder the formation of toxic intermediates and boost acetaminophen detoxification in the liver (Xie 2016). Fu (2018)  discovered that α-mangostin notably suppressed acetaminophen-induced oxidative stress; α-mangostin, a xanthone derivative found in the pericarp of mangosteen fruit, also reduced  inflammatory response through the anti-inflammatory mechanism mediated by the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways. Lu (2018) demonstrated that licochalcone A isolated from the root of Glycyrrhiza glabra had a protective effect on acetaminophen-induced liver injury through the Nrf2-mediated oxidative stress defense mechanism.
 
Saponins
Xu (2017) discovered that the antioxidant, anti-apoptotic, and anti-inflammatory actions of saponins (ginsenosides) had a protective effect on acetaminophen-induced liver injury in mice. Hu (2017) found that ginsenoside Rk1 pretreatment of acetaminophen-induced liver injury in mice significantly lowered levels of the lipid peroxidation product MDA. By increasing Bcl-2 and reducing Bax protein expression, ginsenoside Rk1 impeded activation of the apoptosis pathway. In Ning (2018), ginsenoside Rg1 prevented acetaminophen-induced liver injury through in vivo and in vitro activation of the Nrf2 signaling pathway. Leng (2018) proved that Platycodon grandiflorum saponins had pronounced protective effects on acetaminophen-induced liver injury through the NF-κB and AMPK/PI3K/Akt signaling pathways.

Organic acids 
In Heidari (2016), taurine effectively relieved acetaminophen-induced liver injury and its complications in mice. Jiang (2017) established that, by reducing thiobarbituric acid reactive substances (TBARS) which form as a byproduct of lipid peroxidation and reducing iNOS, COX-2, TNF-2, IL-12, and IL-6, the acids from Potentilla chinensis inhibited inflammation and oxidative stress to alleviate acetaminophen-induced liver injury. Cha (2018) discovered that p-coumaric acid (an abundant isomer of hydroxycinnamic acid widely found in fruits and vegetables) suppressed acetaminophen-induced hepatocyte apoptosis by modulating the MAPK signaling axis in a reactive oxygen species (ROS)-dependent manner and by alleviating response and inflammation from ROS-mediated DNA damage . 

Terpenoid compounds  
In Uchida (2017), compounds in the essential oil of Cymbopogon citratus (lemongrass) hindered neutrophil migration and antioxidant activity in mice with acetaminophen-induced liver injury, thus relieving hepatotoxicity. The research of Zhang (2017) proved that by inhibiting the TNF-α-mediated JNK signaling pathway and the phosphorylation ERK and P38 pathways, pretreatment with astaxanthin (natural sources include shrimp, algae, yeast, and salmon) reduced hepatocellular necrosis, blocked the formation of ROS, prevented oxidative stress, and diminished cellular apoptosis, protecting the liver and alleviating drug-induced liver injury. In Yoshioka  (2017), kamebakaurin (isolated from Rabdosia excisa) improved hepatotoxicity from acetaminophen overdose by inhibiting lipid peroxidation and inflammatory response in mice. 

Phenylpropanoids 
Fructus schisandrae (schisandra fruit) is widely used for liver protection in traditional Chinese medicine and the research of Jiang (2015) proved that lignan components in Fructus schisandrae ameliorated acetaminophen-induced liver injury by inhibiting acetaminophen's CYP-mediated biologic and metabolic pathways. Furthermore, in Jiang (2016) schisandrin B increased liver detoxification and antioxidation by activating the Nrf2/ARE pathway and regulating the Nrf2 target gene, reflecting its hepatoprotective effects. Yan (2018) demonstrated that, by activating sustained autophagy, glycycoumarin relieved acetaminophen-induced oxidative stress and thus prevented liver injury. 

Polysaccharides 
Lin (2018) found that polysaccharides of Dendrobium officinale played a hepatoprotective role by lowering oxidative stress and activating the Nrf2-Keap1 signaling pathway. And in Zhao (2018) the anti-inflammatory effects of polysaccharides of Coreopsis tinctoria regulated the expression of apoptosis-related proteins such as Bax and Bcl-2 to prevent acetaminophen-induced hepatotoxicity. Wu (2018) proved that polysaccharides of Poria cocos played a protective role against acetaminophen-induced liver injury in mice and their molecular mechanism was associated with suppression of the hepatocellular inflammatory response and apoptosis. 

Alkaloids
Li (2014) discovered hepatoprotective effects of berberine on liver fibrosis via activation of AMP-activated protein kinase; and Zhao (2018) found that berberine had pronounced prophylactic effects on acetaminophen-induced hepatotoxicity by inhibiting oxidative stress, hepatocellular necrosis, and inflammatory response. In Park (2016), the alkaloids of Aconitum carmichaelii  protected the organism against acetaminophen-induced injury by suppressing mitochondrial dysfunction and defending liver cells, although the herb is toxic when taken in excess. In 2018, a trial by Bian confirmed that ligustrazine (an alkaloid isolated from Ligusticum wallichii) improved acetaminophen-induced liver injury in mice by regulating the NF-κF and MAPK signal transduction pathways. 

Other compounds  
In Wangkheirakpam (2018), Auricularia delicata demonstrated antimicrobial, antioxidant, and protective effects on acetaminophen-induced liver injury in rats. In Guo (2018), Rhizoma pinelliae  extract regulated bile acid transporter protein in mice with acetaminophen-induced liver injury. By activating Nrf2 and inhibiting NF-κB signal transduction, Garcinia cambogia extract played a protective role in acetaminophen-induced liver injury in mice (Ibrahim 2018). The antioxidant, anti-inflammatory, and anti-apoptotic actions of tannic acid demonstrated significant hepatoprotective effects on acetaminophen-induced hepatotoxicity in the work of Zhang (2017).  

Acetaminophen is a leading cause of drug-induced liver injury and recent research findings indicate that the use of active ingredients from traditional Chinese medicinal herbs might ameliorate such injury. Research on mechanisms of liver injury and the means by which such compounds protect against and alleviate injury holds promise for future antidotes to drug-induced liver injury. 

Basil, a source of rosmarinic acid

​​Please note: The herb information in this blog is presented for educational purposes only. The use of herbal preparations is not recommended without seeking the advice of a healthcare provider. Substances in herbal preparations may interact with prescription drugs to eliminate therapeutic efficacy or induce toxicity. Contact Integrative Translations for a full list of references.