Effects of 8-aminoquinolines on the ultrastructural morphology of Pneumocystis carinii.
Primaquine and other 8-aminoquinolines are effective against Pneumocystis carinii in culture and animal models but the way(s) in which they affect P. carinii are not known. This study used transmission electron microscopy to observe early effects of 8-aminoquinolines on P. carinii grown with human embryonic lung fibroblasts in microcarrier suspension culture. The 8-aminoquinolines evaluated were primaquine and Walter Reed Army Institute for Research (WR) compounds WR6026, WR238605 and WR242511. Samples of P. carinii were taken at 0, 3, 6, 12, 24 and 48 hours from culture flasks containing selected concentrations of the drugs. Time matched samples from a parallel culture without drug served as controls. All the 8-aminoquinolines produced similar morphologic alterations of the internal structure of P. carinii. Initially, dilatation of the nuclear envelopes and membranous arrays arising from the reticular system were observed. Later, more organisms displayed large arrays of smooth membranous material often presenting a concentric membranous pattern. Subsequently, cellular organization was lost resulting in necrosis. At concentrations tested WR242511 appeared to be the most effective, producing alterations in many trophozoites after 6 hours of exposure; WR6026 appeared to be the least effective with some organisms unaffected after 48 hours. The changes observed are consistent with damage to the reticular system of P. carinii, which might be caused by oxidation by the 8-aminoquinolines or their metabolites.
Department of Pathology, Indiana University School of Medicine, Indianapolis 46202.
M P
MP
Goheen
M S
MS
Bartlett
M M
MM
Shaw
S F
SF
Queener
J W
JW
Smith
D000634:Aminoquinolines / Q000494:pharmacology*; D006801:Humans; D008854:Microscopy, Electron; D011010:Pneumocystis / Q000187:drug effects* / Q000648:ultrastructure; D011319:Primaquine / Q000031:analogs & derivatives / Q000494:pharmacology
D000634:Aminoquinolines; C055852:tafenoquine; C068820:WR 242511; D011319:Primaquine; C080436:8-aminoquinoline