Hexavalent chromium induces hepatocyte apoptosis via regulation of apoptosis signal‐regulating kinase 1/c‐Jun amino‐terminal kinase signaling

Abstract

With the spread of hexavalent chromium (Cr(VI)) contamination, Cr(VI)-induced hepatotoxicity has attracted increasing attention in recent years. To date, however, the exact mechanism of Cr(VI) toxicity remains unclear. In this study, we investigated the role of apoptosis signal-regulating kinase 1 (ASK1)/c-Jun aminoterminal kinase (JNK) in Cr(VI)-induced hepatic toxicity and the possible related mechanisms. AML-12 hepatocyte cell-lines were treated with 0, 1, 4, and 16 μmol/Lof Cr(VI) with or without GS-444271 (an ASK1 inhibitor). Adult male mice were administered with 0, 2, 8, and 32 mg/kg body mass (BM)/day of Cr(VI) for 5 days. The level of hepatocyte apoptosis/proliferation, generation of reactive oxygen species (ROS), and expression levels of mRNAs and proteins related to ASK1/JNK and nuclear factor-E2-related factor 2 (Nrf2) signaling were assessed. Results showed that high Cr(VI) exposure induced hepatocyte apoptosis and liver injury by generation of ROS and down-regulation of Nrf2 signaling. In addition, ASK1/JNK signaling activity was upregulated in the Cr(VI)-treated group. Furthermore, GS-444217 treatment significantly rescued Cr(VI)-induced hepatocyte apoptosis and liver dysfunction in vitro and in vivo by down-regulation of ASK1/JNK signaling. Thus, ASK1/JNK signaling appears to play an important role in Cr(VI)-induced hepatocyte apoptosis and liver injury. This study should help improve our understanding of the mechanism of Cr(VI)-induced liver injury and provide support for future investigations on liver disease therapy.

Aluminum, Arsenic, Beryllium, Cadmium, Chromium, Cobalt, Copper, Iron, Lead, Mercury, Molybdenum, Nickel, Platinum, Thallium, Titanium, Vanadium, and Zinc: Molecular Aspects in Experimental Liver Injury

“…There is now sufficient experimental evidence that chromium triggers apoptosis and promotes inflammation by inhibiting the deacetylation of SIRT1 [ 43 ], which stands for sirtuin (silent mating-type information regulation 2 homolog) as a member of a protein family involved in signaling metabolic regulation. Other, more recent mechanistic proposals focus on signaling processes [ 45 ]. For instance, downregulation of Nrf2 signaling may contribute to hepatocyte apoptosis and ROS-dependent liver injury elicited by Cr 6+ , in addition to ASK1/JNK-signaling activity, which was upregulated.…”

Mechanism of ASK1 involvement in liver diseases and related potential therapeutic targets: A critical pathway molecule worth investigating

“…Cr(VI) in the environment can be absorbed by the human body through the digestive tract and respiratory system, and the liver is the main target organ for Cr(VI) accumulation. When the absorbed Cr(VI) enters hepatocytes, it is reduced to low‐valent Cr and generates a large amount of ROS, thereby activating the ASK1–JNK signaling pathway and leading to hepatocyte apoptosis 71 …”

“…When the absorbed Cr(VI) enters hepatocytes, it is reduced to low-valent Cr and generates a large amount of ROS, thereby activating the ASK1-JNK signaling pathway and leading to hepatocyte apoptosis. 71 Developing drugs targeting apoptosis signal-regulated kinase 1 as effective targets for liver diseases Previous studies have found that direct use of small-molecule inhibitors of p38 or JNK to prevent p38-mediated and JNK-mediated diseases was generally unsuccessful, as targeted disruption of the p38a gene results in severe defects in placental development in mice, resulting in increased homozygous embryos mortality. Additionally, loss of any MAPK pathway members coding genes leads to defects in mouse osteoblast differentiation.…”