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A rapid and transient ROS generation by cadmium triggers apoptosis via caspase-dependent pathway in HepG2 cells and this is inhibited through N-acetylcysteine-mediated catalase upregulation.
Toxicol Appl Pharmacol. 2006 May 01; 212(3):212-23.TA

Abstract

Although reactive oxygen species (ROS) have been implicated in cadmium (Cd)-induced hepatotoxicity, the role of ROS in this pathway remains unclear. Therefore, we attempted to determine the molecular mechanisms relevant to Cd-induced cell death in HepG2 cells. Cd was found to induce apoptosis in the HepG2 cells in a time- and dose-dependent fashion, as confirmed by DNA fragmentation analysis and TUNEL staining. In the early stages, both rapid and transient ROS generation triggered apoptosis via Fas activation and subsequent caspase-8-dependent Bid cleavage, as well as by calpain-mediated mitochondrial Bax cleavage. The timing of Bid activation was coincided with the timing at which the mitochondrial transmembrane potential (MMP) collapsed as well as the cytochrome c (Cyt c) released into the cytosol. Furthermore, mitochondrial permeability transition (MPT) pore inhibitors, such as cyclosporin A (CsA) and bongkrekic acid (BA), did not block Cd-induced ROS generation, MMP collapse and Cyt c release. N-acetylcysteine (NAC) pretreatment resulted in the complete inhibition of the Cd-induced apoptosis via catalase upregulation and subsequent Fas downregulation. NAC treatment also completely blocked the Cd-induced intracellular ROS generation, MMP collapse and Cyt c release, indicating that Cd-induced mitochondrial dysfunction may be regulated indirectly by ROS-mediated signaling pathway. Taken together, a rapid and transient ROS generation by Cd triggers apoptosis via caspase-dependent pathway and subsequent mitochondrial pathway. NAC inhibits Cd-induced apoptosis through the blocking of ROS generation as well as the catalase upregulation.

Authors+Show Affiliations

Research Center for Resistant Cells, College of Medicine, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759, South Korea.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

16169029

Citation

Oh, Seon-Hee, and Sung-Chul Lim. "A Rapid and Transient ROS Generation By Cadmium Triggers Apoptosis Via Caspase-dependent Pathway in HepG2 Cells and This Is Inhibited Through N-acetylcysteine-mediated Catalase Upregulation." Toxicology and Applied Pharmacology, vol. 212, no. 3, 2006, pp. 212-23.
Oh SH, Lim SC. A rapid and transient ROS generation by cadmium triggers apoptosis via caspase-dependent pathway in HepG2 cells and this is inhibited through N-acetylcysteine-mediated catalase upregulation. Toxicol Appl Pharmacol. 2006;212(3):212-23.
Oh, S. H., & Lim, S. C. (2006). A rapid and transient ROS generation by cadmium triggers apoptosis via caspase-dependent pathway in HepG2 cells and this is inhibited through N-acetylcysteine-mediated catalase upregulation. Toxicology and Applied Pharmacology, 212(3), 212-23.
Oh SH, Lim SC. A Rapid and Transient ROS Generation By Cadmium Triggers Apoptosis Via Caspase-dependent Pathway in HepG2 Cells and This Is Inhibited Through N-acetylcysteine-mediated Catalase Upregulation. Toxicol Appl Pharmacol. 2006 May 1;212(3):212-23. PubMed PMID: 16169029.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A rapid and transient ROS generation by cadmium triggers apoptosis via caspase-dependent pathway in HepG2 cells and this is inhibited through N-acetylcysteine-mediated catalase upregulation. AU - Oh,Seon-Hee, AU - Lim,Sung-Chul, Y1 - 2005/09/16/ PY - 2005/04/14/received PY - 2005/07/25/revised PY - 2005/07/26/accepted PY - 2005/9/20/pubmed PY - 2006/6/2/medline PY - 2005/9/20/entrez SP - 212 EP - 23 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 212 IS - 3 N2 - Although reactive oxygen species (ROS) have been implicated in cadmium (Cd)-induced hepatotoxicity, the role of ROS in this pathway remains unclear. Therefore, we attempted to determine the molecular mechanisms relevant to Cd-induced cell death in HepG2 cells. Cd was found to induce apoptosis in the HepG2 cells in a time- and dose-dependent fashion, as confirmed by DNA fragmentation analysis and TUNEL staining. In the early stages, both rapid and transient ROS generation triggered apoptosis via Fas activation and subsequent caspase-8-dependent Bid cleavage, as well as by calpain-mediated mitochondrial Bax cleavage. The timing of Bid activation was coincided with the timing at which the mitochondrial transmembrane potential (MMP) collapsed as well as the cytochrome c (Cyt c) released into the cytosol. Furthermore, mitochondrial permeability transition (MPT) pore inhibitors, such as cyclosporin A (CsA) and bongkrekic acid (BA), did not block Cd-induced ROS generation, MMP collapse and Cyt c release. N-acetylcysteine (NAC) pretreatment resulted in the complete inhibition of the Cd-induced apoptosis via catalase upregulation and subsequent Fas downregulation. NAC treatment also completely blocked the Cd-induced intracellular ROS generation, MMP collapse and Cyt c release, indicating that Cd-induced mitochondrial dysfunction may be regulated indirectly by ROS-mediated signaling pathway. Taken together, a rapid and transient ROS generation by Cd triggers apoptosis via caspase-dependent pathway and subsequent mitochondrial pathway. NAC inhibits Cd-induced apoptosis through the blocking of ROS generation as well as the catalase upregulation. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/16169029/A_rapid_and_transient_ROS_generation_by_cadmium_triggers_apoptosis_via_caspase_dependent_pathway_in_HepG2_cells_and_this_is_inhibited_through_N_acetylcysteine_mediated_catalase_upregulation_ DB - PRIME DP - Unbound Medicine ER -