The development and hepatotoxicity of acetaminophen: reviewing over a century of progress

Abstract

Acetaminophen (APAP) was first synthesized in the 1800s, and came on the market approximately 65 years ago. Since then, it has become one of the most used drugs in the world. However, it is also a major cause of acute liver failure. Early investigations of the mechanisms of toxicity revealed that cytochrome P450 enzymes catalyze formation of a reactive metabolite in the liver that depletes glutathione and covalently binds to proteins. That work led to the introduction of N acetylcysteine (NAC) as an antidote for APAP overdose. Subsequent studies identified the reactive metabolite N-acetyl-p-benzoquinone imine, specific P450 enzymes involved, the mechanism of P450-mediated oxidation, and major adducted proteins. The mechanisms downstream of metabolism remain poorly understood but several events appear critical. These events include development of an initial oxidative stress, reactive nitrogen formation, altered calcium flux, JNK activation and mitochondrial translocation, inhibition of mitochondrial respiration, the mitochondrial permeability transition, and nuclear DNA fragmentation. Additional research is necessary to fill remaining gaps in our knowledge of the toxicity, such as the source of the initial oxidative stress, and to improve our understanding liver regeneration after APAP overdose. A better understanding of these mechanisms may lead to additional treatment options. Even though NAC is an excellent antidote, its effectiveness is limited to the first 16 hours following overdose.

Paracetamol: A Review of Guideline Recommendations

“…Almost all RCTs and meta-analyses reported numbers of adverse events from paracetamol that were inferior to those of NSAIDs and comparable to those of placebo. However, reviews on long-term observational data reported increased cardiovascular, gastrointestinal, and renal adverse events during therapy with paracetamol, especially in the high dose range; cases of acute liver failure have been reported after accidental and unintentional overdose of paracetamol [ 10 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 ]. Acute liver failure is infrequent with an approximate incidence for all causes of 1/million/year and is declining [ 134 ].…”

“…Paracetamol overdose can cause liver damage and failure for which different mechanisms have been suggested [ 136 , 137 , 138 ]. At therapeutic doses, paracetamol is metabolized in the liver primarily by glucuronidation (50–60%) and sulfonation pathways (25–30%) and less by oxidation by cytochrome P450 2E1 (<10%).…”

“…Following the direct hepatotoxic effects of NAPQI, the inflammatory reaction and other critical events contribute to the evolution toward liver regeneration or liver irreversible damage. They include oxidative stress, reactive nitrogen formation, and JNK activation [ 138 ]. A key role is played by platelets that recruit macrophages and neutrophils; it has recently been shown that blocking the platelets C-type lectin-like receptor improves liver regeneration [ 136 ].…”

Paracetamol (Acetaminophen) and the Developing Brain

“…The involvement of mitochondria triggers an oxidative stress cascade that leads to accumulation of reactive oxygen species, formation of peroxynitrite, mitochondrial membrane permeability transition, and ultimately cell death [22]. Acute paracetamol toxicity may be antagonized by restoration of GSH stores via early administration of high-dose Nacetyl-cysteine administration [23]. At a later stage, moderate hypothermia to induce RNA-binding motif protein 3 [24] appears to be a promising strategy that is awaiting clinical evaluation.…”

Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk

“…Conversion of APAP to the reactive metabolite N-acetyl- p -benzo quinoneimine (NAPQI) initiates the hepatotoxicity. NAPQI binds to free sulfhydryl groups on amino acid residues, depleting hepatic glutathione and damaging proteins (Jollow et al, 1973; Mitchell et al, 1973; McGill and Hinson, 2020). The protein binding leads to mitochondrial dysfunction and oxidative stress (Jaeschke, 1990; Cover et al, 2005), which activates the c-Jun N-terminal kinases 1/2 (JNK) and other kinases (Gunawan et al, 2006; Hanawa et al, 2008; Nakagawa et al, 2008; Ramachandran et al, 2013).…”