Genetic analysis of mefloquine-resistant mechanism of Plasmodium falciparum.
We studied DNA sequence polymorphism, expression level of pfmdr1 gene and sensitivity of major antimalarial drugs in both mefloquine sensitive and resistant strains to elucidate mechanism of mefloquine resistance. Mefloquine-resistant 523a R/24 strain exhibited decreased susceptibility to mefloquine, artemisinin and halofantrine whereas increased susceptibility to chloroquine. We found a novel point mutation in pfmdr1 gene of 523a R/24 strain. Moreover, overexpression of mRNA of pfmdr1 has been observed in this strain. In addition, functional analysis by pfmdr1 antisense revealed correlation of mefloquine sensitivity with expression level of pfmdr1. We suggest that gene mutation and overexpression of pfmdr1 may be associated with mechanism of mefloquine resistance.
Nishiyama
Yuko
Y
Faculty of Pharmaceutical Sciences, Okayama Unversity, Tsushima, Okayama 700-8530, Japan.
Okuda
Yohei
Y
Kim
Hye-Sook
HS
Huruta
Takahisa
T
Kimura
Mikio
M
Wataya
Yusuke
Y
D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D015767:Mefloquine / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D000962:Antimalarials; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C513498:Mdr1 protein, Plasmodium falciparum