Acetaminophen-induced liver injury: Molecular mechanism and treatments from natural products

Abstract

Acetaminophen (APAP) is a widely used analgesic and antipyretic over-the-counter medicine worldwide. Hepatotoxicity caused by APAP overdose is one of the leading causes of acute liver failure (ALF) in the US and in some parts of Europe, limiting its clinical application. Excessive APAP metabolism depletes glutathione and increases N-acetyl-p-benzoquinoneimide (NAPQI) levels, leading to oxidative stress, DNA damage, and cell necrosis in the liver, which in turn leads to liver damage. Studies have shown that natural products such as polyphenols, terpenes, anthraquinones, and sulforaphane can activate the hepatocyte antioxidant defense system with Nrf2 as the core player, reduce oxidative stress damage, and protect the liver. As the key enzyme metabolizing APAP into NAPQI, cytochrome P450 enzymes are also considered to be intriguing target for the treatment of APAP-induced liver injury. Here, we systematically review the hepatoprotective activity and molecular mechanisms of the natural products that are found to counteract the hepatotoxicity caused by APAP, providing reference information for future preclinical and clinical trials of such natural products.

Phytic acid attenuates acetaminophen-induced hepatotoxicity via modulating iron-mediated oxidative stress and SIRT-1 expression in mice

“…Acetaminophen is one of the most widely used analgesic and antipyretic over-the-counter drugs in the world ( Lee, 2008 ). Although APAP is considered safe at therapeutic doses, its overdose can induce severe liver toxicity and even death ( Liao et al, 2023 ). APAP overdose hepatotoxicity is the leading cause of acute liver failure ( Yoon et al, 2016 ).…”

Flaxseed Lignan Alleviates the Paracetamol-Induced Hepatotoxicity Associated with Regulation of Gut Microbiota and Serum Metabolome

“…Paracetamol (PAM), also known as N-acetaminophen, is one of the most commonly used analgesic and antipyretic drugs in the world. As an available over-the-counter (OTC) drug in China, PAM is frequently used to mild pain and ease fever caused by virus infection, and many people even overtook it during the COVID-19 pandemic [ 1 ]. With the liver enzyme cytochrome P450 (Cyp2E1) and Cyp1A2PAM, PAM is converted into a highly reactive metabolite named acetyl para benzoquinoneimine (NAPQI) [ 2 ], which could be detoxified into non-toxic glutathione-NAPQI by conjugating with glutathione (GSH) [ 3 ].…”

Comparative analysis of gene expression between mice and humans in acetaminophen-induced liver injury by integrating bioinformatics analysis

“…Acetaminophen (APAP) is the most usually used analgesic and antipyretic drug around the world. More than 60 million Americans are estimated to take APAP-containing products on a weekly basis [ 1 ]. Although therapeutic range would be considered to be safe, its overdose could induce acute liver failure (ALF) and even death [ 2 , 3 ].…”