Noncoding RNAs as therapeutics for acetaminophen-induced liver injury

Abstract

Acetaminophen-induced injury and acute liver failure as a clinically relevant modelAcetaminophen-(APAP) induced acute liver failure (ALF) is a major cause of morbidity and mortality in the US (1). Currently, the major therapeutic is N-acetylcysteine (NAC), which is highly effective when given within 8 h of drug overdose. However, late-presenting patients commonly have poor outcomes, and NAC is not effective in these patients. As such, additional therapeutics are urgently needed to treat late-presenting patients. Critical to the generation of new drugs is the continued development of our understanding of APAP-induced ALF in human patients. While a number of recent papers from our group and others have made considerable advances in understanding mechanisms of toxicity in patients and human hepatocytes (2-5), there is still a lack of actionable therapeutic targets. Liver transplantation is the gold standard procedure for treating late-stage ALF but this operation is expensive and comes with additional costs of lifelong anti-rejection medication. In addition, due to limited donor organs, this therapeutic option is not always available (1). There are also ethical issues to consider as a majority of APAP-induced liver injury cases are due to attempted suicide. It is thus imperative that new modalities of treatment, including novel pharmacological agents, be explored for patients who suffer from drug-induced liver injury and acute liver failure.The mechanisms behind APAP-induced liver injury have been extensively examined over the last 40 years (6,7). APAP is typically non-toxic when taken at therapeutic dosages as it is largely metabolized through phase II metabolism by glucuronosyltransferases (glucuronidation) and sulfotransferases (sulfation), and then excreted via the urine (7).Minor levels of APAP are metabolized by cytochrome P450 2E1 (Cyp2E1), which results in the formation of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) (7). However, when sulfation is saturated (8), additional quantities of APAP are metabolized by Cyp2E1 and NAPQI accumulation initiates liver toxicity. Excess NAPQI causes significant depletion of glutathione, protein adduct formation especially in mitochondria (9,10) and a mitochondrial oxidative and nitrosative stress (11), which is then amplified by translocation of c-Jun N-terminal kinase (JNK) to the mitochondria (12,13). This triggers the opening of the mitochondrial permeability transition pore resulting in collapse of the membrane potential, cessation of ATP formation, and matrix swelling (14). The latter effect results in the outer membrane rupture with release of mitochondrial membrane proteins including apoptosis inducing factor and endonuclease G, which translocate to the nucleus and trigger DNA fragmentation (6). The extensive mitochondrial dysfunction and karyolysis are responsible for the necrotic cell death (6). A number of therapeutics have been proposed based on these mechanisms and the pathways that control them; however, new mechanisms that complement our cu...