New insights into the mechanism of hepatocyte apoptosis induced by typical organophosphate ester: An integrated in vitro and in silico approach

Abstract

Apoptosis is one of the typical features of liver diseases, therefore molecular targets of hepatic apoptosis and regulatory mechanisms need to be further investigated. The caspases play important functions in the execution of apoptosis and many studies have focused on classical caspase-dependent cell death pathways. However, other types of cell death pathways (such as mitochondrial poly (ADP-ribose) polymerase-1 (PARP1) pathway) are suggested to be also as important as the caspase-mediated pathways in reflection of early toxic effects in hepatocytes, which requires additional research. In this work, an approach integrated in silico and in vitro was used to investigate the underlying toxicological mechanisms of hepatocyte apoptosis through the PARP1 dependent cell death pathway induced by triphenyl phosphate (TPP). Docking view showed that TPP could interact with helix αJ to affect the activation of PARP1 as a molecular initial event. In vitro assays suggested some biochemical events downstream of PARP1 activation, such as mitochondrial injury, apoptosis inducing factor (AIF) release, reactive oxygen species (ROS) production, and DNA damage. Moreover, the apoptosis was alleviated when cells were pretreated with PJ34 hydrochloride (PARP1 inhibitor), suggesting the mitochondrial PARP1 dependent pathway played a pivotal role in L02 cells apoptosis. This study indicated that PARP1 was an important molecular target in this process. And it also helped to understand the mechanism of hepatocytes apoptosis, early hepatic toxicity, and even liver diseases.