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Drug-regulated expression of Plasmodium falciparum P-glycoprotein hornologue 1: a putative role for nuclear receptors

Johnson, DJ, Owen, A, Plant, N, Bray, PG and Ward, SA (2008) Drug-regulated expression of Plasmodium falciparum P-glycoprotein hornologue 1: a putative role for nuclear receptors ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 52 (4). 1438 - 1445. ISSN 0066-4804

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Abstract

Acquired resistance to therapeutic agents is a major clinical concern in the prevention/treatment of malaria. The parasite has developed resistance to specific drugs through two mechanisms: mutations in target proteins such as dihydrofolate reductase and the bc1 complex for antifolates and nathoquinones, respectively, and alterations in predicted parasite transporter molecules such as P-glycoprotein homologue 1 (Pgh1) and Plasmodium falciparum CRT (PfCRT). Alterations in the expression of Pgh1 have been associated with modified susceptibility to a range of unrelated drugs. The molecular mechanism(s) that is responsible for this phenotype is unknown. We have shown previously (A. M. Ndifor, R. E. Howells, P. G. Bray, J. L. Ngu, and S. A. Ward, Antimicrob. Agents Chemother. 37:1318-1323, 2003) that the anticonvulsant phenobarbitone (PB) can induce reduced susceptibility to chloroquine (CQ) in P. falciparum, and in the current study, we provide the first evidence for a molecular mechanism underlying this phenomenon. We demonstrate that pretreatment with PB can elicit decreased susceptibility to CQ in both CQ-resistant and CQ-sensitive parasite lines and that this is associated with the increased expression of the drug transporter Pgh1 but not PfCRT. Furthermore, we have investigated the proximal promoter regions from both pfmdr1 and pfcrt and identified a number of putative binding sites for nuclear receptors with sequence similarities to regions known to be activated by PB in mammals. Whole-genome analysis has revealed a putative nuclear receptor gene, providing the first evidence that nuclear receptor-mediated responses to drug exposure may be a mechanism of gene regulation in P. falciparum.

Item Type: Article
Uncontrolled Keywords: Science & Technology, Life Sciences & Biomedicine, Microbiology, Pharmacology & Pharmacy, CONSTITUTIVE ANDROSTANE RECEPTOR, RESPONSIVE ENHANCER MODULE, MULTIDRUG-RESISTANCE GENE, PREGNANE-X-RECEPTOR, CHLOROQUINE RESISTANCE, MALARIA PARASITES, IN-VITRO, HALOFANTRINE RESISTANCE, MEFLOQUINE RESISTANCE, CYTOCHROME P4503A
Related URLs:
Divisions: Faculty of Health and Medical Sciences > Biochemistry and Physiology
Depositing User: Mr Adam Field
Date Deposited: 27 May 2010 14:46
Last Modified: 23 Sep 2013 18:36
URI: http://epubs.surrey.ac.uk/id/eprint/1952

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