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. doi: 10.1016/j.taap.2005.07.018. Epub 2005 Sep 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology*
  • Apoptosis / drug effects*
  • Cadmium / toxicity*
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / enzymology*
  • Carcinoma, Hepatocellular / pathology
  • Caspases / metabolism*
  • Catalase / biosynthesis
  • Cell Line
  • Cell Survival / drug effects
  • DNA Fragmentation
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Environmental Pollutants / toxicity*
  • Humans
  • In Situ Nick-End Labeling
  • Membrane Potentials / drug effects
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects
  • fas Receptor / metabolism


  • Drug Combinations
  • Environmental Pollutants
  • Reactive Oxygen Species
  • fas Receptor
  • Cadmium
  • Catalase
  • Caspases
  • Acetylcysteine