Natural Products for Acetaminophen-Induced Acute Liver Injury: A Review

Abstract

The liver plays a vital role in metabolism, synthesis, and detoxification, but it is susceptible to damage from various factors such as viral infections, drug reactions, excessive alcohol consumption, and autoimmune diseases. This susceptibility is particularly problematic for patients requiring medication, as drug-induced liver injury often leads to underestimation, misdiagnosis, and difficulties in treatment. Acetaminophen (APAP) is a widely used and safe drug in therapeutic doses but can cause liver toxicity when taken in excessive amounts. This study aimed to investigate the hepatotoxicity of APAP and explore potential treatment strategies using a mouse model of APAP-induced liver injury. The study involved the evaluation of various natural products for their therapeutic potential. The findings revealed that natural products demonstrated promising hepatoprotective effects, potentially alleviating liver damage and improving liver function through various mechanisms such as oxidative stress and inflammation, which cause changes in signaling pathways. These results underscore the importance of exploring novel treatment options for drug-induced liver injury, suggesting that further research in this area could lead to the development of effective preventive and therapeutic interventions, ultimately benefiting patients with liver injury caused by medicine.

Keywords: P450 enzymes; acetaminophen; acute liver injury; natural products.

Figure 1

Schematic representation of APAP metabolism in the liver. Upon entering the body, the majority of APAP forms complexes with sulfate and glucuronide, which are then excreted via bile or urine. The remaining portion is metabolized by CYP450 enzymes to form NAPQI, which combines with GSH and is subsequently metabolized by the kidneys. When there is excessive depletion of GSH, NAPQI accumulates in the liver, leading to liver injury. APAP: N-acetyl-p-aminophenol; CYP450: cytochrome P450; NAPQI: N-acetyl-p-benzoquinone imine; GSH: glutathione. This figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 2

Molecular mechanisms underlying APAP-induced hepatocyte injury and death. APAP in hepatocytes is metabolized by cytochrome P450 into N-acetyl-p-benzoquinone imine (NAPQI). High levels of NAPQI deplete GSH stores and form NAPQI–protein complexes, damaging the respiratory chain and enhancing the generation of reactive oxygen species (ROS) such as superoxide. Nitric oxide (NO) within the mitochondria nitrosylates mitochondrial proteins, impairing mitochondrial antioxidant defense function and leading to mitochondrial oxidative stress, as well as the oxidation of proteins such as mitochondrial thioredoxin. Oxidized thioredoxin dissociates from its binding partner ASK1, resulting in the activation of ASK1. Activated ASK1, in conjunction with activated MLK3 via MKK4/7 phosphorylation, activates JNK. Activated JNK translocates to the outer mitochondrial membrane and associates with Sab, leading to the inhibition of mitochondrial electron transfer through Src-mediated signaling, thus amplifying mitochondrial oxidative stress. This leads to a transition in mitochondrial permeability, resulting in the release of intermembrane proteins such as Endo G and AIF. AIF and Endo G translocate to the nucleus, inducing fragmentation of nuclear DNA, ultimately leading to hepatocyte death. APAP: N-acetyl-p-aminophenol; NAPQI: N-acetyl-p-benzoquinone imine; ASK1: apoptosis signal-regulating kinase 1; MLK3: mixed-lineage kinase 3; MKK4/7: mitogen-activated protein kinase 4/7; Endo G: endonuclease G; AIF: apoptosis-inducing factor; JNK: c-jun N-terminal kinase. This figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 3

Summarizes the protective effects of phytochemicals against APAP-induced hepatotoxicity. This figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 4

Structural formulae of phytochemical compounds and crude extracts used in the treatment of APAP-induced acute liver injury in past five years.

Figure 5

Summarizes the protective effects of phytochemicals against APAP-induced hepatotoxicity.