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Pyrrolidine dithiocarbamate augments Hg(2+)-mediated induction of macrophage cell death via oxidative stress-induced apoptosis and necrosis signaling pathways.

Abstract
Exposure to mercury can lead to several injuries in mammals, including immune system dysfunction, and pyrrolidine dithiocarbamate (PDTC), as a metal chelator and antioxidant, has been indicated to increase the cytotoxic effects of toxic metals. However, the toxicological effects and possible mechanisms of mercury in combination with PDTC are mostly unclear. In this study, we showed that PDTC dramatically increase the cytotoxic effect of HgCl(2) on cultured murine macrophages (RAW 264.7 cells). PDTC augmented HgCl(2)-induced cytotoxic effects by facilitating the entry of mercury into the cells. The Hg(2+)/PDTC complex significantly and rapidly increased the formation of reactive oxygen species (ROS) and decreased intracellular glutathione (GSH) levels in these cells. Flow cytometry analysis showed that the numbers of sub-G1 hypodiploid cells and annexin V-FITC binding cells increased after Hg(2+)/PDTC complex exposure, and several features of mitochondria-dependent apoptosis were also induced, including mitochondrial membrane depolarization, cytosolic cytochrome c release, poly(ADP-ribose) polymerase (PARP) and caspase 3/7 activation, and DNA fragmentation. Moreover, both apoptotic and necrotic cells were detected using acridine orange/ethidium bromide dual staining. Meanwhile, depleted intracellular ATP levels and increased lactate dehydrogenase (LDH) release were observed, suggesting the induction of necrotic cell death processes. These Hg(2+)/PDTC complex-induced cytotoxicity-related signals could be reversed by pretreatment with the antioxidant N-acetylcysteine. In conclusion, these results suggest that Hg(2+)/PDTC complex-induced oxidative stress causes macrophage cell death via both apoptosis and necrosis. These findings imply for the first time that PDTC dramatically increases the uptake and toxicological effects of Hg(2+) instead of detoxification.
AuthorsChun-Fa Huang, Shing-Hwa Liu, Shoei-Yn Lin-Shiau
JournalToxicology letters (Toxicol Lett) Vol. 214 Issue 1 Pg. 33-45 (Oct 02 2012) ISSN: 1879-3169 [Electronic] Netherlands
PMID22909951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Biomarkers
  • Pyrrolidines
  • Reactive Oxygen Species
  • Thiocarbamates
  • pyrrolidine dithiocarbamic acid
  • Mercury
Topics
  • Animals
  • Biomarkers
  • Cell Death (drug effects)
  • Cell Line
  • Drug Interactions
  • Gene Expression Regulation (drug effects)
  • Macrophages (drug effects)
  • Mercury (toxicity)
  • Mice
  • Oxidative Stress (drug effects)
  • Pyrrolidines (toxicity)
  • Reactive Oxygen Species
  • Signal Transduction (drug effects)
  • Thiocarbamates (toxicity)

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