Signalling pathways involved in paracetamol-induced hepatotoxicity: new insights on the role of protein tyrosine phosphatase 1B

Abstract

Acute hepatic failure secondary to paracetamol poisoning is associated with high mortality. Paracetamol-induced hepatotoxicity causes oxidative stress that triggers signalling pathways and ultimately leads to lethal hepatocyte injury. We will review the signalling pathways activated by paracetamol in the liver emphasizing the role of protein tyrosine phosphatase 1B (PTP1B) in the balance between cell death and survival in hepatocytes. PTP1B has emerged as a key modulator of the antioxidant system mediated by the nuclear factor erythroid-2-related factor 2 (Nrf2) in hepatic cells in response to paracetamol overdose. Also, this phosphatase modulates the classical survival pathways triggered by the activation of the insulin-like growth factor-I (IGF-I) signalling cascade. Therefore, PTP1B is a novel therapeutic target against paracetamol-induced liver failure.

Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes

“…At the molecular level, IRS1 and IRS2 that connect the IR/IGF-IR with downstream survival signaling in hepatocytes [26,52] are negatively modulated by PA and this effect was prevented by LA co-and post-treatment. This is a critical issue which links the activation of JNK and p38 MAPK by oxidative and/or ER stress [14,80,81] with an early serine phosphorylation of IRS proteins that triggers proteosomal degradation [81,82].…”

“…Treatment of mouse hepatocytes with PA decreased cellular viability and this effect was ameliorated by co-treatment with LA (SupplementaryFigure 3A). Taking into account that phosphorylation of JNK triggers the degradation of insulin receptor substrate 1 (IRS1) and 2 (IRS2), and the relationship between degradation of IRSs and reduction of hepatocyte viability previously reported by our group[26,52], degradation of both IRS1 and IRS2induced by PA at 16-24 h was suppressed in cells co-treated with PA and LA ϭϳ (Supplementary…”

Ameliorative Effect of Citrus Lemon Peel Extract and Resveratrol on Premature Ovarian Failure Rat Model: Role of iNOS/Caspase-3 Pathway

“…Furthermore, our findings implied that giving CPA to normal rats produced a large rise in MDA levels and a significant decline in GSH and SOD levels comparable to those of normal rats. This could be due to CPA toxicity in producing different pathological abnormalities, including oxidative stress damage, apoptosis, and inflammation [37], thus, oxidative stress triggered by the deactivation and depression of antioxidant enzymes [38]. This result is consistent with those of [39], who attributed the elevation of MDA levels and the depletion in GSH and SOD levels to the interfering of acrolein with antioxidant defense systems, impeding nuclear and cytoplasmic development of oocytes and causing apoptosis are two ways in which oxidative stress can contribute to ovarian failure via impairment of CYP450.…”

Evaluation of the Reparative Effect of Sinomenine in an Acetaminophen-Induced Liver Injury Model

“…APAP administration increased ROS production, and the initiation of oxidative stress may result in hepatotoxicity [30]. The pathogenesis of liver diseases is significantly influenced by oxidative stress, marked by elevated MDA levels and reduced GSH levels [31]. In a study conducted by Li L [32], they describe that SIN exhibits a protective effect on rat cardiomyocytes by reducing the content of MDA and enhancing the activity of SOD in response to a free radical-induced injury.…”