Polyamine metabolism in Pneumocystis carinii.
Alpha-difluoromethylornithine (DFMO) is being used to treat Pneumocystis carinii pneumonia despite a lack of in vitro evidence supporting its antipneumocystis activity. DFMO is a specific inhibitor of ornithine decarboxylase, the rate-limiting enzyme of polyamine biosynthesis. To investigate polyamine metabolism in P. carinii, extracts of the organism were analyzed for polyamine content and ornithine decarboxylase activity, and [3H]ornithine and [14C]arginine incorporation into polyamines during short-term culture was determined. P. carinii extracts contained putrescine and spermidine in a ratio of 0.17:1; traces of spermine were detected. Although ornithine decarboxylase activity was not detected, P. carinii incorporated ornithine and arginine into putrescine and spermidine but not into spermine, suggesting that the spermine detected derived from contaminating host cells. Uninfected rat lung incorporated ornithine minimally. Pentamidine, DFMO, and alpha-monofluoromethyldehydroornithine methyl ester inhibited ornithine incorporation by up to 86% at clinically achievable concentrations. These data provide a rationale for using polyamine synthesis antagonists in P. carinii pneumonia and a method for screening antipneumocystis drugs in vitro.
Lipschik
G Y
GY
Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892.
Masur
H
H
Kovacs
J A
JA
D000818:Animals; D001120:Arginine / Q000378:metabolism; D000518:Eflornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D008168:Lung / Q000382:microbiology; D009952:Ornithine / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000032:analysis; D065108:Ornithine Decarboxylase Inhibitors; D010419:Pentamidine / Q000494:pharmacology; D011010:Pneumocystis / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000378:metabolism; D051381:Rats; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism
D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D013096:Spermine; D010419:Pentamidine; D001120:Arginine; D009952:Ornithine; D009955:Ornithine Decarboxylase; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine