Lmb. Ursos et al., Antimalarial drugs influence the pH dependent solubility of heme via apparent nucleation phenomena, MOL BIOCH P, 112(1), 2001, pp. 11-17
Recently, we measured a more acid digestive vacuolar pH for drug resistant
Plasmodium falciparum [Dzekunov S, Ursos LMB, Roepe PD. Mol Biochem Parasit
ol 2000;in press; Ursos LMB, Dzekunov S, Roepe PD. Mol Biochem Parasitol 20
00;in press]. We suggested this acidification contributes to drug resistanc
e via the profound effects that pH has on the solubility of unpolymerized h
eme found in the vacuole (ferriprotoporphyrin IX mu oxo dimers). In this re
port, we measure how FPIX concentration, time, NaCl concentration, and seve
ral antimalarial drugs affect FPIX pH dependent solubility. Aggregation is
essentially instantaneous below pH 5.3, but at vacuolar pH previously measu
red for HB3 parasites [Dzekunov S, Ursos LMB, Roepe PD. Mol Biochem Parasit
ol 2000;in press] can increase to several minutes as NaCl is lowered. As FP
IX is decreased, the midpoint of the pH dependent solubility curve shifts t
o higher values. Addition of antimalarial drugs also increases the midpoint
of the pH dependent FPIX solubility curve, with the net shift proportional
to the relative affinity of the drug for FPIX. Surprisingly, however, for
all drugs tested shifts of essentially identical magnitude are found at all
drug: FPIX molar ratios inspected, spanning eight orders of magnitude (to
as low as 0.0000001:1). This suggests that changes in pH dependent FPIX sol
ubility by addition of antimalarial drugs is via previously unrecognized dr
ug/FPIX nucleation phenomena. These data could have important implications
for understanding the role of previously observed changes in pH(vac) [Dzeku
nov S, Ursos LMB, Roepe PD. Mol Biochem Parasitol 2000;in press; Ursos LMB,
Dzekunov S, Roepe PD. Mol Biochem Parasitol 2000;in press] upon developmen
t of antimalarial drug resistance. (C) 2001 Elsevier Science B.V. All right
s reserved.