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Title: The role of Leishmania enriettii multidrug resistance protein 1 (LeMDR1) in mediating drug resistance is iron-dependent
Authors: Wong, ILK
Chow, LMC 
Keywords: Leishmania enriettii
Multidrug resistance
Iron transporter
Iron(II) sulfate
Bathophenanthroline disulfonic acid
Issue Date: 2006
Publisher: Elsevier
Source: Molecular and biochemical parasitology, 2006, v. 150, no. 2, p. 278-287 How to cite?
Journal: Molecular and biochemical parasitology 
Abstract: In parasitic protozoan Leishmania enriettii, the role of a multidrug resistance (mdr) gene LeMDR1 (L. enriettii multidrug resistance 1) in mediating vinblastine resistance has been previously demonstrated by association, transfection and “gene knockout” studies. LeMDR1 has been shown to be located intracellularly and it was proposed to mediate drug resistance by sequestering drugs into intracellular organelles rather than by active efflux. Here we compared LeMDR1 overexpressed cell lines (Vint3 and V160), wild type (Le) and LeMDR1 “double knockout” mutant (LeMDR1−/−) and demonstrated that LeMDR1 gene copy number was associated with (1) higher level of intracellular iron, (2) increased sensitivity to an iron-dependent antibiotic, streptonigrin and (3) increased enzyme activity of an iron–sulfur-containing mitochondrial enzyme, aconitase. This result suggests that the normal function of LeMDR1 is related to mitochondrial iron homeostasis. To test such hypothesis, we have used the LeMDR1-overexpressing mutant V160 and LeMDR1−/− mutant to determine how iron level can affect its resistance level to drugs targeting either cytosol (vinblastine) or mitochondria (rhodamine 123 and pentamidine). It was found that the resistance level of V160 to vinblastine can be increased by iron whereas resistance to both rhodamine 123 and pentamidine can be increased by iron depletion and vice versa. Iron treatment can potentiate rhodamine 123 and pentamidine accumulation whereas iron deprivation can cause the reduction of rhodamine 123 accumulation. Our result highly suggests that LeMDR1's function in mediating drug resistance is iron-dependent.
ISSN: 0166-6851
DOI: 10.1016/j.molbiopara.2006.08.014
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