EXPLORE!

Liver Update: Alcohol and drug-induced liver injury: Metabolism, mechanisms, pathogenesis and potential therapies.

  1294 Views

eMediNexus    19 August 2021

The liver serves as a major metabolic organ in the body, metabolizing carbohydrates, proteins, amino acids, lipids, drugs and xenobiotics. Thus it often faces insults relating to drug and xenobiotics-induced damage. 

Asia sees numerous cases of liver injury induced by using herbal or traditional medicine. In addition, drug-induced liver injury (DILI), alcohol abuse and alcoholic liver disease (ALD) are other health problems globally. 

The pathogenesis of ALD progresses from alcoholic steatosis to alcoholic hepatitis (AH), liver fibrosis, cirrhosis and ultimately hepatocellular carcinoma (HCC). Besides, there are no promising treatments for ALD.

The liver possesses drug-metabolizing enzymes including phase I enzymes (mainly cytochrome P450 (CYP) oxidases), phase II reactions (conjugation enzymes) and phase III excretion (transporters). The CYP3A family enzymes metabolize almost half of the currently prescribed drugs.  

With CYP-mediated phase I metabolism, phase II enzymes also have key roles in the biotransformation of drugs/xenobiotics. A group of researchers rendered novel insights on the role of nuclear hepatocyte nuclear factor 4alpha (HNF4α) in the regulation of cholesterol sulfotransferase 2B1b (SULT2B1b) and their impact on hepatic glucose homeostasis. Obesity and the transition from fasting to the fed state are known to increase the hepatic expression of SULT2B1b which further inhibits HNF4α, causing a decrease in glucose production and gluconeogenic gene expression. Interestingly, there is evidence that suggests a negative feedback loop between SULT2B1b and HNF4α in the regulation of glucose homeostasis. Therefore, phase III enzymes, such as SULT2B1b play an important role in regulating drug metabolism and also in regulating energy homeostasis, particularly gluconeogenesis.

Acetaminophen (APAP) maximally undergoes glucuronidation and sulfation and is secreted to bile and plasma from the liver, while a smaller portion is metabolized by CYP2E1 to generate a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which further conjugates with liver glutathione (GSH) to be detoxified. overdose of APAP causes the excessive generation of NAPQI that depletes hepatocellular GSH and then covalently binds to intracellular proteins to form APAP-adducts (APAP-AD). mitochondrial APAP-AD leads to mitochondrial damage and subsequent necrosis and liver injury. Thus mitochondrial damage is regarded as the key event resulting in APAP-induced necrosis and liver injury. 

A study describes recent progress on targeting mitochondrial and mitochondrial biogenesis for ameliorating APAP-induced liver injury. Activation of c-Jun N-terminal kinase (JNK) especially that of mitochondria is associated with APAP-induced hepatocyte necrosis. Post-treatment with 4-methylpyrazole (4 MP) does not affect oxidative metabolism and protein adduct formation but significantly attenuate APAP-induced mitochondrial translocation of JNK and liver injury. 

Increasing peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) by SRT1720 or recombinant fibroblast growth factor 21 (FGF21) attenuates APAP-induced liver injury by increasing mitochondrial biogenesis and liver regeneration, indicating targeting mitochondrial biogenesis to be a promising approach for treating APAP-induced liver injury.

Another type of DILI to be discussed is idiosyncratic, which is considered unpredictable and can even occur in a therapeutic dose. Recent evidence suggests that Kupffer cells and infiltrating macrophages may promote liver regeneration to ameliorate DILI.

Pyrrolizidine alkaloids (PAs), the ester derivatives of necine base and necic acid, are found in a majority of herbal plants. PAs are predominantly metabolized in the liver by CYP3A, generating reactive metabolites dehydropyrrolizidine alkaloids (DHPAs), which is further hydrolyzed to dehydroretronecine (DHR) when it binds to cellular GSH to form GSH-conjugates. As GSH is depleted, DHPAs and DHR bind to proteins to form pyrrole-protein adducts to initiate the hepatotoxicity likely by inducing mitochondrial fragmentation in hepatocytes. PAs can damage the parenchymal cells and the non-parenchyma cells.

Chronic alcohol consumption induces the accumulation of hepatic lipid droplets (LDs), by increased uptake of circulating free fatty acids, increased de novo lipogenesis, decreased mitochondria beta-oxidation, and very-low-density lipoprotein (VLDL) secretion as well as deceased autophagic degradation of LDs via impaired lipophagy.

Lysosome have shown their role in the regulation of LD homeostasis after alcohol. Along with the autophagy-lysosomal pathway, the ubiquitin-proteasome system (UPS) is another cellular catabolism pathway. alcohol consumption can impair both autophagy and UPS in the liver resulting in the accumulation of LDs and Mallory-Denk bodies and liver injury.

Dietary enrichment in the n-6 PUFA and linoleic acid have been shown to exacerbate liver injury in experimental ALD. Microbiome dysbiosis can induce short-chain fatty acid changes, alter bile acid metabolism, impair intestinal barrier function, and increase the release of bacterial and fungal products resulting in inflammation and contributing to the pathogenesis of ALD. Thus therapies targeting the microbiome, including dietary nutrient interference, herbal medicine, antibiotics, anti-fungal agents, probiotics, engineered bacterial therapy, fecal transplantation, oral hygiene and bacteriophage are widely utilized for the prevention and treatment of ALD.

Pharmacological inhibitors for RIP1 and RIP3, targeting RIP1-RIP3-MLKL-mediated necroptosis can aid the use of steatotic liver for liver transplantation by improving ischemia-reperfusion liver injury.

Source: Ding WX, Yang L. Alcohol and drug-induced liver injury: Metabolism, mechanisms, pathogenesis and potential therapies. Liver Res. 2019;3(3-4):129-131. doi:10.1016/j.livres.2019.11.006

To comment on this article,
create a free account.

Sign Up to instantly get access to 10000+ Articles & 1000+ Cases

Already registered?

Login Now

Most Popular Articles

News and Updates

eMediNexus provides latest updates on medical news, medical case studies from India. In-depth medical case studies and research designed for doctors and healthcare professionals.