The role of apoptosis in acetaminophen hepatotoxicity

Abstract

Although necrosis is recognized as the main mode of cell death induced by acetaminophen (APAP) overdose in animals and humans, more recently an increasing number of publications, especially in the herbal medicine and dietary supplement field, claim an important contribution of apoptotic cell death in the pathophysiology. However, most of these conclusions are based on parameters that are not specific for apoptosis. Therefore, the objective of this review was to re-visit the key signaling events of receptor-mediated apoptosis and APAP-induced programmed necrosis and critically analyze the parameters that are being used as evidence for apoptotic cell death. Both qualitative and quantitative comparisons of parameters such as Bax, Bcl-2, caspase processing and DNA fragmentation in both modes of cell death clearly show fundamental differences between apoptosis and cell death induced by APAP. These observations together with the lack of efficacy of pan-caspase inhibitors in the APAP model strongly supports the conclusion that APAP hepatotoxicity is dominated by necrosis or programmed necrosis and does not involve relevant apoptosis. In order not to create a new controversy, it is important to understand how to use these "apoptosis" parameters and properly interpret the data. These issues are discussed in this review.

Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability

“…Specifically, our findings indicate that death of intestinal cells is an early event following APAP intoxication, is strictly limited to the crypts, and predominantly affects epithelial stem cell populations. However, we found that hepatocyte cell death occurred by an apoptosis‐independent mechanism, a finding that is consistent with previous reports . Together, these observations indicate that APAP intoxication can induce differential modes of injury across the intestine and liver and suggest that intestinal injury may be a neglected complication suffered by patients during APAP‐induced ALF with potential implications on overall outcome.…”

“…For instance, a somewhat controversial topic is the relative contributions of the various forms of cell death (e.g., apoptosis, necrosis, pyroptosis) . Even to this day, publications report conflicting evidence either in favor of or against a role of hepatic apoptosis in APAP hepatotoxicity . Although this topic was not the focus of the current study, our data provide the strongest support to the argument that direct hepatic injury due to APAP toxicity is primarily driven by necrotic cell death.…”

“…However, we found that hepatocyte cell death occurred by an apoptosis-independent mechanism, a finding that is consistent with previous reports. (15) Together, these observations indicate that APAP intoxication can induce differential modes of injury across the intestine and liver and suggest that intestinal injury may be a neglected complication suffered by patients during APAP-induced ALF with potential implications on overall outcome.…”

Mito-tempo protects against acute liver injury but induces limited secondary apoptosis during the late phase of acetaminophen hepatotoxicity

“…Interestingly, however, some previously assumed specific parameters of apoptosis, such as mitochondrial bax translocation, mitochondrial cytochrome c release, BH3 interacting domain death agonist (bid) cleavage and DNA strand breaks (TUNEL and DNA ladder), are all detected during APAP hepatotoxicity (Adams et al 2001; Bajt et al 2008; Cover et al, 2005; Jaeschke and Bajt 2006; Lawson et al 1999; Ray et al 1990). Use of these parameters has led to the assumption in some earlier studies and also more recently that apoptosis is a relevant cell death mechanism in the toxicity (El-Hassan et al 2003; Hu et al 2017; Wang et al 2018, Zhang et al 2017), while in reality none of these parameters is specific for apoptosis, and all of them can also be observed in cell necrosis (Jaeschke et al 2018; Jaeschke and Lemasters 2003; Krassl-Graup et al 1995). On the other hand, this also raises the intriguing question “why does APAP cause exclusive necrosis rather than apoptosis despite the appearance of these classical apoptotic parameters?”…”

“…More importantly, this minor caspase activation never resulted in noticeable apoptotic cell death and a caspase inhibitor did not protect against the overall cell death (Williams et al 2011). Thus, there is very limited evidence for apoptosis as a primary mode of cell death during APAP-induced liver injury in mice or humans (Jaeschke et al 2018). …”