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

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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.

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Acknowledgments

We thank our colleagues Dr. Barry Rosen (Wayne State University) and Dr. Zijuan Liu (Oakland University) for useful and instructive discussions of the topics covered by this manuscript. The research presented here was supported by NIH grant R01 010845-01A2 to M.S., by US EPA Cooperative Agreement CR829522 and by the Clinical Nutrition Research Center Grant DK 56350. This manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does mention of trade names or commercial products constitutes endorsement or recommendation for use.

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  1. Weibing Xing

    Present address: Duke Clinical Research Institute, Duke University Medical Center, Duke University, Durham, NC, 27715, USA

Authors and Affiliations

  1. Department of Nutrition, University of North Carolina at Chapel Hill, CB# 7461, 2302 MHRC, Chapel Hill, NC, 27599-7461, USA

    Zuzana Drobná, Felecia S. Walton, David S. Paul & Miroslav Stýblo

  2. Curriculum in Toxicology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Weibing Xing

  3. Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, 27709, USA

    David J. Thomas

  4. Center for Environmental Medicine, Asthma, and Lung Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-2774, USA

    Miroslav Stýblo

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  1. Zuzana Drobná
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Correspondence to Miroslav Stýblo.

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Drobná, Z., Walton, F.S., Paul, D.S. et al. Metabolism of arsenic in human liver: the role of membrane transporters. Arch Toxicol 84, 3–16 (2010). https://doi.org/10.1007/s00204-009-0499-7

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