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Transport of Arsenic by the Human Multidrug Resistance Proteins Open Access


Other title
multidrug resistance
Type of item
Degree grantor
University of Alberta
Author or creator
Carew, Michael W
Supervisor and department
Leslie, Elaine (Physiology)
Examining committee member and department
Vore, Mary (Toxicology, University of Kentucky)
Cheeseman, Chris (Physiology)
Casey, Joe (Biochemistry)
Weinfeld, Mike (Oncology)
Department of Physiology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
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.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Carew MW, Leslie EM: Selenium-dependent and -independent transport of arsenic by the human multidrug resistance protein 2 (MRP2/ABCC2): implications for the mutual detoxification of arsenic and selenium. Carcinogenesis 2010, 31(8):1450-1455.Carew MW, Naranmandura H, Shukalek CB, Le XC, Leslie EM: Monomethylarsenic diglutathione transport by the human multidrug resistance protein 1 (MRP1/ABCC1). Drug Metab Dispos 2011, 39(12):2298-2304.

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