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Insights into the carcinogenic mode of action of arsenic

A D Kligerman1, A H Tennant

  • 1Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, B143-06 US Environmental Protection Agency Research Triangle Park, NC 27711, USA. kligerman.andrew@epa.gov

Toxicology and Applied Pharmacology
|November 23, 2006
PubMed

Insights

Arsenic causes cancer by damaging DNA and disrupting cell division. New research shows glutathione reduces arsenic to a form that disrupts tubulin, potentially leading to chromosome aberrations and cancer.

Area of Science:

  • Toxicology
  • Molecular Biology
  • Cancer Research

Background:

  • Arsenic's carcinogenicity in humans is known, but its mechanisms of action (MOA) are debated.
  • Previous studies indicate arsenicals cause DNA damage and spindle disruption, but are poor mutagens.

Purpose of the Study:

  • To review previous findings on arsenic's genotoxicity and spindle disruption.
  • To present new evidence on arsenic's interaction with glutathione (GSH) and tubulin polymerization.
  • To propose a hypothesis for arsenic-induced chromosome aberrations (CAs) and cancer.

Main Methods:

  • Review of prior research on DNA damage and mutation induction by arsenicals.
  • Experimental investigation of reduced glutathione (GSH) effects on arsenicals.
  • Analysis of tubulin polymerization disruption and reactive oxygen species (ROS) involvement.
  • Hypothesis formulation for arsenic's role in chromosome aberrations.

Main Results:

  • Reduced glutathione (GSH) chemically reduces pentavalent arsenicals to trivalent forms.
  • Trivalent arsenicals disrupt tubulin polymerization, affecting cell division.
  • Reactive oxygen species (ROS) are unlikely to be involved in tubulin disruption.
  • Arsenic may induce stable chromosome aberrations (CAs) leading to cancer.

Conclusions:

  • Arsenic's carcinogenicity involves disruption of tubulin polymerization via GSH-mediated reduction.
  • Genetic damage, specifically chromosome aberrations, is a likely component of arsenic's MOA.
  • Further research is needed to fully elucidate arsenic's carcinogenic pathways.

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