Archives of Toxicology

, Volume 84, Issue 1, pp 3–16 | Cite as

Metabolism of arsenic in human liver: the role of membrane transporters

  • Zuzana Drobná
  • Felecia S. Walton
  • David S. Paul
  • Weibing Xing
  • David J. Thomas
  • Miroslav Stýblo
Review Article

Abstract

Metabolism of inorganic arsenic (iAs) is one of the key factors determining the character of adverse effects associated with exposure to iAs. Results of previous studies indicate that liver plays a primary role in iAs metabolism. This paper reviews these results and presents new data that link the capacity of human hepatocytes to metabolize iAs to the expression of specific membrane transporters. Here, we examined relationship between the expression of potential arsenic transporters (AQP9, GLUT2, P-gp, MRP1, MRP2, and MRP3) and the production and cellular retention of iAs and its methylated metabolites in primary cultures of human hepatocytes exposed for 24 h to subtoxic concentrations of arsenite. Our results show that the retention of iAs and methylarsenic metabolites (MAs) by hepatocytes exposed to sub-micromolar concentrations of arsenite correlates negatively with MRP2 expression. A positive correlation was found between MRP2 expression and the production of dimethylarsenic metabolites (DMAs), specifically, the concentration of DMAs in culture media. After exposures to high micromolar concentrations of arsenite which almost completely inhibited MAs and DMAs production, a positive correlation was found between the expression of GLUT2 and cellular retention of iAs and MAs. MRP3, AQP9, or P-gp expression had no effect on the production or distribution of iAs, MAs, or DMAs, regardless of the exposure level. Hepatocytes from seven donors used in this study did not contain detectable amounts of MRP1 protein. These data suggest that MRP2 plays an important role in the efflux of DMAs, thus, regulating kinetics of the methylation reactions and accumulation of iAs and MAs by human hepatocytes. The membrane transport of iAs by high-capacity GLUT2 transporters is not a rate-limiting step for the metabolism of arsenite at low exposure level, but may play a key role in accumulation of iAs after acute exposures which inhibit iAs methylation.

Keywords

Arsenic Human liver Membrane transport 

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Zuzana Drobná
    • 1
  • Felecia S. Walton
    • 1
  • David S. Paul
    • 1
  • Weibing Xing
    • 2
    • 3
  • David J. Thomas
    • 4
  • Miroslav Stýblo
    • 1
    • 5
  1. 1.Department of NutritionUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Curriculum in ToxicologyThe University of North Carolina at Chapel HillChapel HillUSA
  3. 3.Duke Clinical Research InstituteDuke University Medical Center, Duke UniversityDurhamUSA
  4. 4.Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and DevelopmentUS Environmental Protection AgencyResearch Triangle ParkUSA
  5. 5.Center for Environmental Medicine, Asthma, and Lung BiologyThe University of North Carolina at Chapel HillChapel HillUSA

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