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

Journal of Biochemical and Molecular Toxicology - Tập 18 Số 3 - Trang 133-142 - 2004
Chin-Ju J. Hsiao1, Susan R. Stapleton1,2
1Department of Biological Sciences, Western Michigan University, Kalamazoo, MI 49008, USA
2Department of Chemistry, Western Michigan University, Kalamazoo, MI 49008, USA

Tóm tắt

AbstractThe 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

Từ khóa


Tài liệu tham khảo

IARC (International Agency for Research on Cancer).Beryllium cadmium mercury and exposure in the glass manufacturing industry. In:IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.Lyon France:IRAC Scientific Publications;1993. Vol58 pp41–117.

10.1016/S0300-483X(99)00013-X

10.1002/jbt.10062

10.1074/jbc.275.15.11418

10.1152/ajplung.2000.279.6.L1005

10.1016/S0006-2952(02)01112-7

10.1016/S0891-5849(99)00166-5

10.1016/S0300-483X(02)00245-7

10.1016/S0163-7258(00)00114-5

10.1038/nrm715

10.1074/jbc.270.28.16483

10.1093/carcin/20.11.2063

10.1074/jbc.274.29.20251

10.1016/S0006-2952(99)00406-2

10.1006/taap.2000.9114

10.1006/taap.2001.9214

10.1016/S0955-0674(97)80068-3

10.1093/toxsci/50.1.98

10.1006/taap.1999.8829

10.1016/0300-9084(93)90147-K

10.1016/0092-8674(80)90238-X

10.1242/jcs.112.16.2765

10.1016/S0891-5849(00)00429-9

10.1016/S0169-328X(99)00168-0

10.1006/excr.1997.3825

10.1053/jhep.2003.50233

Vernhet L, 2001, Arsenic induces expression of the multidrug resistance‐associated protein 2 (MRP2) gene in primary rat and human hepatocytes, J Pharmacol Exp Ther, 298, 234

10.1016/S0304-3835(97)04680-6

10.1016/S0278-6915(00)00117-4

10.1016/S0008-6363(03)00428-0

10.1016/S0167-4889(02)00195-7

10.1016/S0898-6568(02)00026-8

10.1016/S0006-2952(01)00694-3

10.1016/S0165-5728(00)00359-3

10.1053/jhep.2003.50135

10.1016/S0006-291X(03)01287-7

10.1016/S1368-7646(03)00043-8

10.1016/S0301-0082(99)00042-8

Chuang SM, 2000, Roles of JNK, p38 and ERK mitogen‐activated protein kinases in the growth inhibition and apoptosis induced by cadmium, Carcinogensis, 21, 1423, 10.1093/carcin/21.7.1423

10.1016/S0898-6568(03)00117-7

10.1016/S0165-5728(02)00055-3

10.1006/cyto.2002.1034

10.1016/S0041-008X(02)99499-8

10.1016/S0891-5849(03)00387-3

Thông tin
Thông tin xuất bản

Journal of Biochemical and Molecular Toxicology

Tập 18 Số 3

133-142

Thông tin tác giả