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Cadmium-induced apoptosis in murine macrophages is antagonized by antioxidants and caspase inhibitors.
J Toxicol Environ Health A. 2006 Jun; 69(12):1181-201.JT

Abstract

Cadmium is a toxic heavy metal that accumulates in the environment and is commonly found in cigarette smoke and industrial effluents. This study was designed to determine the role of reactive oxygen species (ROS) generation, and its antagonism by antioxidants, in cadmium-mediated cell signaling and apoptosis in murine macrophage cultures. Cadmium-generated ROS production was observed in J774A.1 cells at 6 h, reverting to control levels at 16 and 24 h. The ROS production was concentration related between 20 and 500 microM cadmium. Activation of caspase-3 was observed at 8 h and DNA fragmentation at 16 h in the presence of 20 microM cadmium, suggesting that caspase-3 activation is a prior step to DNA fragmentation in cadmium-induced apoptosis. Inhibitors of caspase-3, -8, -9, and a general caspase inhibitor suppressed cadmium-induced caspase-3 activation and apoptosis indicating the importance of caspase-3 in cadmium-induced toxicity in these cells. Protection against the oxidative stress with N-acetylcysteine (NAC) and silymarin (an antioxidant flavonoid) blocked cadmium-induced apoptosis. Pretreatment of cells with NAC and silymarin prevented cadmium-induced cell injury, including growth arrest, mitochondrial impairment, and necrosis, and reduced the cadmium-elevated intracellular calcium ([Ca2+]i), suggesting that the oxidative stress is a source of increased [Ca2+]i. NAC inhibited cadmium-induced activation of mitogen-activated protein kinases, the c-Jun NH2-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK). However, silymarin provided only a partial protection for JNK activation, and only at the low concentration did it inhibit cadmium-induced ERK activation. Inhibition of caspase-3 protected oxidative stress produced by cadmium, suggesting that the activation of caspase-3 also contributes to generation of reactive oxygen species (ROS). Results emphasized the role of ROS, Ca2+ and mitogen-activated protein kinases in cadmium-induced cytotoxicity in murine macrophages.

Authors+Show Affiliations

Program in Toxicology, Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602-7389, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16728380

Citation

Kim, Jiyoung, and Raghubir P. Sharma. "Cadmium-induced Apoptosis in Murine Macrophages Is Antagonized By Antioxidants and Caspase Inhibitors." Journal of Toxicology and Environmental Health. Part A, vol. 69, no. 12, 2006, pp. 1181-201.
Kim J, Sharma RP. Cadmium-induced apoptosis in murine macrophages is antagonized by antioxidants and caspase inhibitors. J Toxicol Environ Health A. 2006;69(12):1181-201.
Kim, J., & Sharma, R. P. (2006). Cadmium-induced apoptosis in murine macrophages is antagonized by antioxidants and caspase inhibitors. Journal of Toxicology and Environmental Health. Part A, 69(12), 1181-201.
Kim J, Sharma RP. Cadmium-induced Apoptosis in Murine Macrophages Is Antagonized By Antioxidants and Caspase Inhibitors. J Toxicol Environ Health A. 2006;69(12):1181-201. PubMed PMID: 16728380.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cadmium-induced apoptosis in murine macrophages is antagonized by antioxidants and caspase inhibitors. AU - Kim,Jiyoung, AU - Sharma,Raghubir P, PY - 2006/5/27/pubmed PY - 2006/6/23/medline PY - 2006/5/27/entrez SP - 1181 EP - 201 JF - Journal of toxicology and environmental health. Part A JO - J Toxicol Environ Health A VL - 69 IS - 12 N2 - Cadmium is a toxic heavy metal that accumulates in the environment and is commonly found in cigarette smoke and industrial effluents. This study was designed to determine the role of reactive oxygen species (ROS) generation, and its antagonism by antioxidants, in cadmium-mediated cell signaling and apoptosis in murine macrophage cultures. Cadmium-generated ROS production was observed in J774A.1 cells at 6 h, reverting to control levels at 16 and 24 h. The ROS production was concentration related between 20 and 500 microM cadmium. Activation of caspase-3 was observed at 8 h and DNA fragmentation at 16 h in the presence of 20 microM cadmium, suggesting that caspase-3 activation is a prior step to DNA fragmentation in cadmium-induced apoptosis. Inhibitors of caspase-3, -8, -9, and a general caspase inhibitor suppressed cadmium-induced caspase-3 activation and apoptosis indicating the importance of caspase-3 in cadmium-induced toxicity in these cells. Protection against the oxidative stress with N-acetylcysteine (NAC) and silymarin (an antioxidant flavonoid) blocked cadmium-induced apoptosis. Pretreatment of cells with NAC and silymarin prevented cadmium-induced cell injury, including growth arrest, mitochondrial impairment, and necrosis, and reduced the cadmium-elevated intracellular calcium ([Ca2+]i), suggesting that the oxidative stress is a source of increased [Ca2+]i. NAC inhibited cadmium-induced activation of mitogen-activated protein kinases, the c-Jun NH2-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK). However, silymarin provided only a partial protection for JNK activation, and only at the low concentration did it inhibit cadmium-induced ERK activation. Inhibition of caspase-3 protected oxidative stress produced by cadmium, suggesting that the activation of caspase-3 also contributes to generation of reactive oxygen species (ROS). Results emphasized the role of ROS, Ca2+ and mitogen-activated protein kinases in cadmium-induced cytotoxicity in murine macrophages. SN - 1528-7394 UR - https://www.unboundmedicine.com/medline/citation/16728380/Cadmium_induced_apoptosis_in_murine_macrophages_is_antagonized_by_antioxidants_and_caspase_inhibitors_ L2 - https://www.tandfonline.com/doi/full/10.1080/15287390600631144 DB - PRIME DP - Unbound Medicine ER -