No abstract

Synopsis Drug induced liver injury (DILI) represents a broad spectrum of liver manifestations. However, the most common manifestation is hepatocyte death following drug intake. DILI can be predictable and dose dependent with notable example of acetaminophen toxicity. Idiosyncratic DILI occurs in an unpredictable fashion at low frequencies implying that environmental and genetic factors alter the susceptibility of individuals to the insult (drugs). An biochemical stress is usually initiated by drugs and their reactive metabolites through covalent binding or direct damage to mitochondria, which leads to oxidative stress, activation of stress signaling pathways, impairment of mitochondrial function, endoplasmic reticulum stress, etc. The ultimate cell death pathways converges at mitochondria through acting on mitochondrial outer-membrane permeability (MOMP) or mitochondrial permeability transition (MPT). The striking HLA associations with idiosyncratic DILI highlight the critical role of the adaptive immune response in pathogenesis, which is now believed to be unmasked in genetically susceptible individuals by the biochemical stress in the liver triggered by drug and/or metabolites. The drug-induced biochemical stress may also contribute to the severity of injury by sensitizing hepatocytes to the lethal effects of the immune response. Adaptive mechanisms including antioxidant signaling (such as Nrf2 signaling) , mitophagy, autophagy, unfolded protein response, anti-inflammatory and immune tolerance dampen and ameliorate injury. All together, the development and severity of injury is determined on the battle between the hazardous stress and adaptive responses within the hepatocytes and the innate and adaptive immune systems.

Drugs that cause liver injury often “stress” mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Due to adaptation, drugs alone rarely cause liver injury, with acetaminophen being the notable exception. Drug-induced liver injury (DILI) usually involves other extrinsic factors, such as the adaptive immune system, that cause “stressed” hepatocytes to become injured; leading to idiosyncratic DILI, the rare and unpredictable adverse drug reaction in the liver. Hepatocyte injury, due to drug and extrinsic insult, causes a second wave of signaling changes associated with adaptation, cell death, and repair. If the stress and injury reach a critical threshold, then death signaling pathways such as JNK become dominant and hepatocytes enter a failsafe mode to undergo self-destruction. DILI can be seen as an active process involving recruitment of death signaling pathways that mediate cell death rather than a passive process due to overwhelming biochemical injury. In this review, we highlight the role of signal transduction pathways, which frequently involve mitochondria, in the development of DILI.

With the high prevalence of obesity, diabetes, and other features of the metabolic syndrome in United States, nonalcoholic fatty liver disease (NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis (NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor (TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH.

REAL-OCT has a significantly enhanced pharmacological effect, and this is most likely due to the favorable changes in the pharmacokinetic parameters upon lipidization. The observed liver targeting effect of REAL-TOC suggests that REAL-OCT might be advantageous over OCT in treating liver cancers.