Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls

Abstract

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions.

Activation of the eIF2α-ATF4 Pathway by Chronic Paracetamol Treatment Is Prevented by Dietary Supplementation with Cysteine

“…Previous studies and our data show that chronic treatment with APAP decreased liver GSH [4]. The APAP-induced decrease in hepatic GSH is basically interpreted as the irreversible loss of GSH after conjugation with NAPQI and its elimination as mercapturates in the urine [21]. In acute toxicity, GSH is also used for peroxynitrite scavenging [27].…”

“…APAP is a widely used analgesic and antipyretic drug, safe when used at standard doses and for the shortest period possible. However, overdose leads to hepatotoxicity and even acute liver failure [21], and long-term treatments at the upper standard therapeutic doses had been shown to be associated with adverse events [22]. Our previous studies shed light on muscle wasting in response to chronic treatment with APAP inducing Cys/GSH deficiency without being toxic [23].…”

“…APAP is a widely used analgesic and antipyretic drug, safe when used at standard doses and for the shortest period possible. However, overdose leads to hepatotoxicity and even acute liver failure [21], and long-term treatments at the upper standard therapeutic…”

Probiotics: Evolving as a Potential Therapeutic Option against Acetaminophen-Induced Hepatotoxicity

“…GSH generally detoxifies ROS and RNS, thus GSH depletion caused by NAPQI potentiates the accumulation of these free radicals [ 41 ]. An increase in oxidative stress enhances mitochondrial membrane permeability resulting in a decrease in mitochondrial membrane potential and hampers ATP production [ 42 ]. In addition, NAPQI can directly interact with the α-subunit of ATP-synthase resulting in an impairment of ATP synthesis [ 43 ].…”

“…Phosphorylated-JNK undergoes translocation to the mitochondria and binds to Sab located on the mitochondrial outer membrane, which further endorses the production of superoxide from ETC. JNK also triggers the translocation of Bax into mitochondria, which further decreases the integrity of the mitochondrial membrane and, as a consequence, endonuclease G, cytochrome C, and apoptosis-inducing factor (AIF) are released into the cytosol [ 42 , 44 , 45 ]. AIF and endonuclease G can contribute to DNA fragmentation after translocating to the nucleus [ 42 , 44 , 45 ].…”