Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions

Abstract

Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in many developed countries. Mitochondrial oxidative stress is considered to be the predominant cellular event in APAP-induced liver injury. Accordingly, N-acetyl cysteine, a known scavenger of reactive oxygen species (ROS), is recommended as an effective clinical antidote against APAP-induced acute liver injury (AILI) when it is given at an early phase; however, the narrow therapeutic window limits its use. Hence, the development of novel therapeutic approaches that can offer broadly protective effects against AILI is clearly needed. To this end, it is necessary to better understand the mechanisms of APAP hepatotoxicity. Up to now, in addition to mitochondrial oxidative stress, many other cellular processes, including phase I/phase II metabolism, endoplasmic reticulum stress, autophagy, sterile inflammation, microcirculatory dysfunction, and liver regeneration, have been identified to be involved in the pathogenesis of AILI, providing new targets for developing more effective therapeutic interventions against APAP-induced liver injury. In this review, we summarize intracellular and extracellular events involved in APAP hepatotoxicity, along with emphatic discussions on the possible therapeutic approaches targeting these different cellular events.

Glycycoumarin protects mice against acetaminophen‐induced liver injury predominantly via activating sustained autophagy

“…Although it was generally thought that the protective role of autophagy in acetaminophen toxicity was limited to the oxidative damage phase and primarily targeted at damaged mitochondria (Ni et al, , ), our result revealed a sustained activation of autophagy after GCM treatment, which was even observed 12 h post‐acetaminophen challenge, after oxidative stress had already developed. This suggests that a late stage mechanism, such as suppression of ER stress, might be involved in the autophagy‐mediated hepataprotective effect of GCM (Yan et al, ). Although the precise mechanism by which GCM exerts its therapeutic effect against acetaminophen hepatotoxicity in the late phase remains unclear, we observed a better therapeutic effect of GCM against acetaminophen hepatotoxicity compared with NAC, as revealed by the lower effective dose and wider therapeutic window.…”

Hepatoprotective and antioxidant potential of Pycnogenol® in acetaminophen‐induced hepatotoxicity in rats

“…So, glucose‐6‐phosphate dehydrogenase and pentose phosphate pathways are activated in order to maintain normal NADPH level in hepatocytes. These processes lead to glycogenolysis or, in other words, depletion of glycogen in the liver cell cytoplasm (Gusarov & Nudler, ; Yan, Huo, Yin, & Hu, ). In this study, staining specific for glycogen revealed that APAP administration led to significant consuming of glycogen but to a lesser extent in animals pretreated with PYC.…”

Effect of Liposomal Curcumin on Acetaminophen Hepatotoxicity by Down-regulation of Oxidative Stress and Matrix Metalloproteinases

“…This mechanism leads to in vivo 34: 569-582 (2020) 576 mitochondrial oxidative stress, increased mitochondrial membrane permeability and hepatic cell death (45). Mitochondrial oxidative stress is considered to be the main cellular dysfunction in APAP-induced liver injury (46). In our study, the levels of oxidative stress molecules (NOx and MDA) significantly increased after APAP administration (250 mg/kg) (Table II, Figures 4 and 5).…”

“…The hepatoprotective effect of LCC could be linked to its already proven inhibitory effect on iNOS activity (52) and MDA production (51) as well as its ability to maintain the thiol pool (53) and to improve catalase production (54). In addition to mitochondrial oxidative stress, many other cellular processes, including inflammation, microcirculatory dysfunction and extracellular matrix degradation, have been shown to be involved in the pathogenesis of APAP-induced liver injury (46,55).…”