Premium
Characterization of Cd‐induced molecular events prior to cellular damage in primary rat hepatocytes in culture: Activation of the stress activated signal protein JNK and transcription factor AP‐1
Author(s) -
Hsiao Chinju J.,
Stapleton Susan R.
Publication year - 2004
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.20018
Subject(s) - c jun , reactive oxygen species , kinase , microbiology and biotechnology , glutathione , transcription factor , oxidative stress , activator (genetics) , chemistry , lactate dehydrogenase , cadmium chloride , dna damage , biochemistry , biology , cadmium , enzyme , receptor , dna , gene , organic chemistry
Abstract The effect of Cadmium (Cd) on the expression of c‐Jun N ‐terminal kinase (JNK), c‐jun , and activator protein‐1 (AP‐1) has been investigated. We previously reported that Cd causes cell damage as indicated by increases in the cytotoxic parameters, lactate dehydrogenase and lipid peroxidation, and this damage was mediated by decreases in cellular concentration of glutathione. In the present study, we investigate the molecular events involved prior to the Cd‐induced cellular toxicity and damage in primary rat hepatocytes. We propose that Cd, through the generation of reactive oxygen species (ROS) and prior to significant cellular damage, activates the stress activated signal protein JNK, regulates c‐jun expression, and promotes the binding of a redox sensitive transcription factor AP‐1. We show JNK activity and c‐jun mRNA level significantly increased at 1 h and AP‐1 DNA binding activity significantly enhanced at 3 h in the presence of 4 μM cadmium chloride. Blocking the Cd induction of JNK activity, c‐jun mRNA level, and AP‐1 binding activity using the antioxidants N ‐acetyl cysteine (10 mM) or carnosol (0.5 μg/mL) suggests a role for ROS. Blocking JNK activity and c‐jun mRNA by SP600125 (20 μM), a JNK inhibitor, supports the role of JNK in transmission of signals induced by Cd. © 2004 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:133–142, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20018