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. Significant gaps remain in our understanding of the mechanisms downstream of metabolism, 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 complete our knowledge of the toxicity, such as the source of the initial oxidative stress, and to greatly improve our understanding of 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.

Keywords:

• Acetaminophen overdose
• APAP-protein adducts
• biomarkers
• drug-induced liver injury
• drug metabolism
• liver injury
• liver regeneration
• mitochondria
• oxidative stress
• reactive nitrogen

Disclosure statement

JAH is Chief Scientific Officer of Acetaminophen Toxicity Diagnostics, LLC (ATD). MRM serves as a consultant for ATD. The company had no role in the funding, preparation, or submission of this manuscript.

Additional information

Funding

This work was supported by the Association for the Study of Liver Diseases Foundation (AASLD Foundation) under a 2018 Pinnacle Research Award (MRM) and by the National Institutes of Health under grant NIDDK 5R42DK079387 (JAH; PI: Laura P. James, MD).