title: In vitro selection of halofantrine resistance in Plasmodium falciparum is not associated with increased expression of Pgh1.
abstract: Recent investigations into quinoline and phenanthrene methanol resistance in Plasmodium falciparum have described a linkage between amplification of the mdr homologue pfmdr1 and decreased susceptibility to mefloquine (MQ) and halofantrine (HF). We have examined the current theories on cross-resistance patterns and pfmdr1 gene expression by comparing the chloroquine (CQ) resistant isolate K1 with K1Hf, developed from the K1 isolate by intermittent exposure to halofantrine. Reduced halofantrine susceptibility in K1Hf was accompanied by reduced sensitivity to mefloquine and increased sensitivity to chloroquine. These sensitivity changes were reflected by changes in parasite drug accumulation. The loss of high level chloroquine resistance in K1Hf was associated with an inability of verapamil to enhance chloroquine sensitivity or accumulation. In contrast verapamil retained the chemosensitising potential against quinine in this isolate. The changes in phenotype were achieved without any amplification or increased expression of pfmdr1 or reversion of the Tyr86 mutation in the gene. Our data indicates that acquisition of halofantrine and mefloquine resistance and the loss of high level chloroquine resistance can be achieved without enhanced expression of the pfmdr1 gene product.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, UK.
authors.forename: G Y
authors.initials: GY
authors.lastname: Ritchie
authors.forename: M
authors.initials: M
authors.lastname: Mungthin
authors.forename: J E
authors.initials: JE
authors.lastname: Green
authors.forename: P G
authors.initials: PG
authors.lastname: Bray
authors.forename: S R
authors.initials: SR
authors.lastname: Hawley
authors.forename: S A
authors.initials: SA
authors.lastname: Ward
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001692:Biological Transport; D002738:Chloroquine / Q000378:metabolism / Q000494:pharmacology; D016172:DNA Fingerprinting; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000235:genetics*; D018628:Gene Dosage; D015870:Gene Expression; D015151:Immunoblotting; D015767:Mefloquine / Q000494:pharmacology; D010616:Phenanthrenes / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D015800:Protozoan Proteins / Q000096:biosynthesis* / Q000235:genetics; D011803:Quinine / Q000378:metabolism / Q000494:pharmacology; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D014700:Verapamil / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D010616:Phenanthrenes; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine; D011803:Quinine; D014700:Verapamil; C023768:halofantrine; D015767:Mefloquine