Basis of antimalarial action: non-weak base effects of chloroquine on acid vesicle pH
Biologically active concentrations of chloroquine increase the pH of the parasite's acid vesicles within 3-5 min. This increase in pH results from two mechanisms, one of which is markedly reduced in chloroquine-resistant parasites. Because chloroquine is a weak base, it increases vesicle pH by that mechanism in chloroquine-susceptible and resistant parasites and mammalian cells (based on its two pKs and on the delta pH between the acid vesicle and the extracellular environment). In chloroquine-susceptible parasites, but not resistant parasites or mammalian cells, chloroquine increases the pH of acid vesicles 700- to 800-fold more than can be accounted for by its properties as a weak base. The increase in acid vesicle pH caused by these non-weak base effects of nanomolar chloroquine in susceptible parasites suggests that chloroquine acts by interfering with acid vesicle functions in the parasite such as the endocytosis and proteolysis of hemoglobin, and the intracellular targeting of lysosomal enzymes. The non-weak base effects of nanomolar chloroquine on parasite vesicle pH are also responsible for its safety because these chloroquine concentrations do not affect mammalian cells.
- Research Organization:
- Washington Univ. School of Medicine, St. Louis, MO
- OSTI ID:
- 6570778
- Journal Information:
- Am. J. Trop. Med. Hyg.; (United States), Vol. 2
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
SENSITIVITY
MALARIA
ETIOLOGY
PLASMODIUM
QUINOLINES
BIOLOGICAL EFFECTS
LYSOSOMES
MAMMALS
PH VALUE
PROTONS
ANIMALS
AROMATICS
AZAARENES
AZINES
BARYONS
CELL CONSTITUENTS
DISEASES
ELEMENTARY PARTICLES
FERMIONS
HADRONS
HETEROCYCLIC COMPOUNDS
INFECTIOUS DISEASES
INVERTEBRATES
MICROORGANISMS
NUCLEONS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANOIDS
PARASITES
PARASITIC DISEASES
PROTOZOA
PYRIDINES
SPOROZOA
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology
550900 - Pathology