An overdose of acetaminophen (APAP), known as paracetamol, can cause severe liver damage and
acute liver failure. Excessive intake of APAP exceeds normal metabolic pathways, results in
glutathione depletion within hepatocytes and formation of cytotoxic protein adducts which lead to
hepatocyte death and liver inflammation. To date, N-Acetylcysteine (NAC), a glutathione precursor,
is the only pharmacological therapy. However, its efficacy decreases with increasing time between
overdose and treatment and liver transplantation is the only life-saving option for patients that
present too late. Thus, novel therapeutic options are an important medical need. Our group has
previously identified metallothioneins (MTs) as danger signals which are released from dying cells,
attract other immune cells to the site of injury and sustain the inflammatory response. The
pathogenesis of APAP-induced liver injury is critically influenced by the inflammatory response
following hepatocyte death. Therefore, we believe that inhibiting MTs’ danger signaling function by
using anti-MT antibodies could deliver a novel therapeutic option for APAP overdosed patients. In
this project, we will use human samples, a mouse model and in vitro assays to investigate the
therapeutic potential of anti-MT antibodies on APAP-induced liver damage in time, in combination
with and in comparison to NAC.