Acetaminophen-induced apoptosis: Facts versus fiction

An overdose of the widely used analgesic acetaminophen (APAP) is the most common cause of acute liver failure in the western world and hence is a clinically significant problem. Thus, mechanisms of APAP-induced hepatotoxicity have been the focus of extensive investigation for decades and it was established that APAP induces hepatocyte cell death by necrosis. Although APAP-induced necrosis shares some features of apoptosis induced by the intrinsic pathway, apoptotic cell death in this context was ruled out due to the absence of caspase activation and lack of protection by caspase inhibitors and missing morphological characteristics of apoptotic cells. Deeper mechanistic understanding of the cell death process after APAP in recent years has now revealed that cells die by programmed necrosis and apoptosis is not a relevant mode of cell death in this context. Hence, it is alarming to note that an increasing number of studies are being published purporting to indicate that APAP induces apoptotic cell death. These papers broadly measure “apoptotic markers” with questionable specificity such as Bax, Bcl-2 and caspase-3 protein expression, or use the terminal deoxynucleotidyl transferase dUTP nick end labeling assay as basis for the conclusion that there is apoptosis after APAP overdose. The misguided use of these apoptosis parameters in correlative studies without context or scientific rationale confuses the field and threatens to undo decades of careful mechanistic investigation into this topic. This review examines this emerging problem in detail and recommends approaches to correct it. RELEVANCE FOR PATIENTS: Hepatotoxicity and acute liver failure caused by an acetaminophen overdose is a serious clinical problem in western countries. Understanding the mode of cell death and the signaling pathways involved is critical for developing new therapeutic approaches. Recent trends to claim that apoptosis is a relevant mode of cell death in acetaminophen hepatotoxicity are not justified by sound scientific data and will not lead to effective new drug development.