Acetaminophen hepatotoxicity: A mitochondrial perspective

Abstract

Acetaminophen (APAP) is a highly effective analgesic, which is safe at therapeutic doses. However, an overdose can cause hepatotoxicity and even liver failure. APAP toxicity is currently the most common cause of acute liver failure in the United States. Decades of research on mechanisms of liver injury have established the role of mitochondria as central players in APAP-induced hepatocyte necrosis and this chapter examines the various facets of the organelle's involvement in the process of injury as well as in resolution of damage. The injury process is initiated by formation of a reactive metabolite, which binds to sulfhydryl groups of cellular proteins including mitochondrial proteins. This inhibits the electron transport chain and leads to formation of reactive oxygen species, which induce the activation of redox-sensitive members of the MAP kinase family ultimately causing activation of c-Jun N terminal kinase, JNK. Translocation of JNK to the mitochondria then amplifies mitochondrial dysfunction, ultimately resulting in mitochondrial permeability transition and release of mitochondrial intermembrane proteins, which trigger nuclear DNA fragmentation. Together, these events result in hepatocyte necrosis, while adaptive mechanisms such as mitophagy remove damaged mitochondria and minimize the extent of the injury. This oscillation between recovery and necrosis is predominant in cells at the edge of the necrotic area in the liver, where induction of mitochondrial biogenesis is important for liver regeneration. All these aspects of mitochondria in APAP hepatotoxicity, as well as their relevance to humans with APAP overdose and development of therapeutic approaches will be examined in detail in this chapter.

Keywords: Drug toxicity; Hepatocyte; Liver; Necrosis; Nitric oxide; Superoxide.

Fig 1–. Peroxynitrite formation is critical for initial mitochondrial dysfunction and signaling to the cytosol:

The mitochondrial electron transport chain (ETC) comprised of 4 proteins transfer electrons from complex I to complex 4, while pumping protons to generate a proton gradient which is utilized by ATP synthase (complex V) to generate ATP. Though free radicals such as superoxide are generated during electron transport, superoxide dismutases (SOD) within the mitochondria scavenge them efficiently. Thus, reaction of superoxide with nitric oxide (NO) generated from neuronal NOS and probably eNOS on mitochondria is minimal. When mitochondria are exposed to NAPQI, adduct formation on mitochondrial proteins such as ATP synthase could result in reverse electron transport within the ETC, which elevates superoxide generation. Protein adduct formation on anti-oxidant enzymes prevents efficient scavenging of superoxide, which enables its reaction with nitric oxide to form peroxynitrite radicals. These in turn can modify enzymes such as SOD as well as spill out of the mitochondria into the cytosol, probably through outer membrane protein such as VDAC.

Fig 2–. JNK and Bax translocation to mitochondria amplify mitochondrial dysfunction:

Phosphorylated JNK as well as Bax translocate to the mitochondria and JNK binds to its ligand Sab, on the outer mitochondrial membrane. This binding initiates a signaling cascade which inhibits the ETC and further amplifies superoxide and peroxynitrite generation. This in turn activates the mitochondrial permeability transition pore on the inner membrane, of which cyclophilin D is a component. This, along with the formation of Bax pores on the outer membrane allow release of mitochondrial proteins such as endonuclease G and apoptosis inducing factor (AIF) into the cytosol.