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Transport of Arsenic by the Human Multidrug Resistance Proteins

  • Author / Creator
    Carew, Michael W
  • Arsenic is a potent environmental contaminant and human carcinogen, occurring naturally in the earth’s crust and entering the food chain through leeching into the water supply. Upon entering the body, inorganic arsenic is methylated to mono- and di-methylated forms, the trivalent versions of which have been shown to have increased toxicity over their inorganic counterparts. The majority of arsenic is methylated in the liver and is eliminated from the body in urine. Multidrug resistance protein 2 (MRP2) can transport the seleno-bis(S-glutathionyl) arsinium ion, [(GS)2AsSe]-, and coupled with the apical expression of MRP2 in the liver, provides a mechanistic explanation for the cooperative detoxification observed between arsenic and selenium. Multidrug resistance protein 1 (MRP1) was capable of transporting monomethylarsenic diglutathione (MMA(GS)2) and due to the broad tissue distribution of MRP1, is likely to be important for protecting cells from arsenic. Multidrug resistance protein 4 (MRP4) can transport MMA(GS)2 and dimethylarsinic acid (DMAV) and due to its basolateral localization in the hepatocyte and apical localization in the renal proximal tubule, is likely crucial in the disposition of arsenic from the liver into the blood stream and then into urine. The results of this thesis demonstrate the role and the importance of MRP1, MRP2, and MRP4 in the protection against arsenic and its metabolites.

  • Subjects / Keywords
  • Graduation date
    2014-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3H10V
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Physiology
  • Supervisor / co-supervisor and their department(s)
    • Leslie, Elaine (Physiology)
  • Examining committee members and their departments
    • Vore, Mary (Toxicology, University of Kentucky)
    • Cheeseman, Chris (Physiology)
    • Weinfeld, Mike (Oncology)
    • Casey, Joe (Biochemistry)