Bavachinin Induces Oxidative Damage in HepaRG Cells through p38/JNK MAPK Pathways.

Shan Wang,Xiao Sun,Xiaobo Sun,Min Wang,Guibo Sun,Yu Tian

doi:10.3390/toxins10040154

Shan Wang, Xiao Sun + Show 4 more

Open Access

https://doi.org/10.3390/toxins10040154

Copy DOI

Abstract

Drug-induced liver injury is one of the main causes of drug non-approval and drug withdrawal by the Food and Drug Administration (FDA). Bavachinin (BVC) is a natural product derived from the fruit of the traditional Chinese herb Fructus Psoraleae (FP). There have been reports of acute liver injury following the administration of FP and its related proprietary medicines. To explore BVC hepatotoxicity and its mechanisms, we used the HepaRG cell line. In our recent research, we showed that BVC induces HepaRG cell death, mainly via BVC-induced oxidative damage. The formation of ROS is closely related to the activation of the stress-activated kinases, JNK and p38, while SP600125 (SP, JNK inhibitor) and SB203580 (SB, p38 inhibitor) pretreatment inhibited the generation of ROS. On the other hand, N-acetylcysteine (NAC) pretreatment prevented the phosphorylation of p38 but not that of JNK. Taken together, these data reveal that BVC induces HepaRG cell death via ROS and the JNK/p38 signaling pathways.

Highlights

Drug-induced liver injury (DILI) is a major challenge for clinicians, the pharmaceutical industry and regulatory agencies worldwide, including the Food and Drug Administration (FDA) [1]
To investigate the cytotoxic effects of various concentrations of BVC on the HepaRG cell line, we performed MTT assays after 24, 36, 48 and 60 h of BVC treatment, and the results showed that BVC inhibited cell viability in a time- and dose-dependent manner (Figure 1B)
D, the phosphorylation of p38 peaked at 1 h and declined at 3, 6, and 9 h; the phosphorylation of jun N-terminal kinases (JNKs) (Figure 3E,F) increased in a time-dependent manner during the early stage (1, 3, and 6 h), peaked at 6 h, and decreased at 9 h. These results revealed that p38 and JNK are both activated after the HepaRG cell line is exposed to BVC. p38 was mainly involved in the early stage (0–1 h), and JNK was involved in the later phase (1–9 h)

Summary

Introduction

Drug-induced liver injury (DILI) is a major challenge for clinicians, the pharmaceutical industry and regulatory agencies worldwide, including the FDA [1]. DILI typically manifests in a very small subset of the population under treatment with no clear dose relationship and is termed an idiosyncratic event [2]. The major challenge is that, for many compounds that cause human DILI, the underlying mechanisms are not yet fully understood. Its idiosyncratic character makes predicting DILI in preclinical tests very challenging [6]. In vitro systems used to address DILI have consisted of HepG2 or Huh. Primary hepatocyte models have evolved as the gold standard to address drug safety-related questions in vitro due to their superior functionality and liver-like phenotype

Methods

Results

Conclusion