Ciach Michelle, Zong Kathleen, Kain Kevin C, Crandall Ian
Tropical Disease Unit, Toronto General Hospital, Toronto, Ontario, Canada.
Antimicrob Agents Chemother. 2003 Aug;47(8):2393-6. doi: 10.1128/AAC.47.8.2393-2396.2003.
Quinoline resistance in malaria is frequently compared with P-glycoprotein-mediated multidrug resistance (mdr) in mammalian cells. We have previously reported that nonylphenolethoxylates, such as NP30, are potential Plasmodium falciparum P-glycoprotein substrates and drug efflux inhibitors. We used in vitro assays to compare the ability of verapamil and NP30 to sensitize two parasite isolates to four quinolines: chloroquine (CQ), mefloquine (MF), quinine (QN), and quinidine (QD). NP30 was able to sensitize (reversal, >80%) P. falciparum to MF, QN, QD, and, to a lesser extent, CQ. The presence of 2 micro M verapamil had no effect on mefloquine resistance; however, the presence of verapamil modulated the activities of QN and QD in a manner parallel to that observed for CQ. Genetic analysis of putative quinoline resistance genes did not suggest an association between known point mutations in pfcrt and pfmdr1 and NP30 sensitization activity. We conclude that the sensitization action of NP30 is distinct both phenotypically and genotypically from that of verapamil.
疟疾中的喹啉耐药性常与哺乳动物细胞中P-糖蛋白介导的多药耐药性（mdr）相比较。我们之前报道过，壬基酚聚氧乙烯醚，如NP30，是恶性疟原虫P-糖蛋白的潜在底物和药物外排抑制剂。我们使用体外试验比较维拉帕米和NP30使两种寄生虫分离株对四种喹啉（氯喹（CQ）、甲氟喹（MF）、奎宁（QN）和奎尼丁（QD））敏感的能力。NP30能够使恶性疟原虫对MF、QN、QD以及在较小程度上对CQ敏感（逆转，>80%）。2微摩尔/升维拉帕米的存在对甲氟喹耐药性没有影响；然而，维拉帕米的存在以与观察到的氯喹相似的方式调节了奎宁和奎尼丁的活性。对假定的喹啉耐药基因的遗传分析并未表明pfcrt和pfmdr1中已知的点突变与NP30敏感活性之间存在关联。我们得出结论，NP30的敏感化作用在表型和基因型上均与维拉帕米不同。
