Effect of nicotine on lung S-adenosylmethionine and development of Pneumocystis pneumonia.
Because S-adenosylmethionine (AdoMet) is required by Pneumocystis carinii in vitro, Pneumocystis infection depletes plasma AdoMet of rats and humans, nicotine reduces AdoMet of guinea pig lungs, and smoking correlates with reduced episodes of Pneumocystis pneumonia (PCP) in AIDS patients, we tested the effect of nicotine treatment on PCP using a rat model. Intraperitoneal infusion of 400 microg of R-(+) nicotine kg(-1) h(-1) intraperitoneal for 21 days caused a 15-fold reduction in lung AdoMet although neither plasma nor liver were changed. Infusion of 4 and 400 microg kg(-1) h(-1) into immunosuppressed rats, beginning when rats were inoculated with P. carinii, caused 85 and 99.88% reductions, respectively, in P. carinii cysts at sacrifice 21 days later; P. carinii nuclei were reduced by 91.2 and >99.99%, respectively. This effect was reversed by concomitant administration of AdoMet with nicotine. Treatment with AdoMet alone increased infection intensity. We conclude that AdoMet is a critical and limiting nutrient for Pneumocystis thus can serve as a therapeutic target for PCP. Regarding the mechanism, nicotine treatment caused no change in rat lung activity of AdoMet synthesizing methionine ATP transferase activity nor was there any evidence of increased AdoMet utilization for methylation reactions. Except of a doubling of putrescine, nicotine treatment also did not change lung polyamine content. However, key polyamine anabolic and catabolic enzymes were upregulated, and there were corresponding changes in polyamine metabolic intermediates. We conclude that chronic nicotine treatment increases lung polyamine catabolic/anabolic cycling and/or excretion leading to increased AdoMet-consuming polyamine biosynthesis and depletion of lung AdoMet.
Shivji
Mehboob
M
Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, New York 10010, USA.
Burger
Suzanna
S
Moncada
Camilo Andres
CA
Clarkson
Allen B
AB
Merali
Salim
S
D000818:Animals; D015180:Electrophoresis, Gel, Two-Dimensional; D020869:Gene Expression Profiling; D006168:Guinea Pigs; D006801:Humans; D007091:Image Processing, Computer-Assisted; D020128:Inhibitory Concentration 50; D007525:Isoelectric Focusing; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D008716:Methionine Adenosyltransferase / Q000378:metabolism; D009538:Nicotine / Q000737:chemistry / Q000494:pharmacology*; D011010:Pneumocystis / Q000378:metabolism; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy / Q000378:metabolism*; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism; D016133:Polymerase Chain Reaction; D040901:Proteomics / Q000379:methods; D051381:Rats; D012436:S-Adenosylmethionine / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors; D014357:Trypsin / Q000494:pharmacology; D015854:Up-Regulation
D011073:Polyamines; D009538:Nicotine; D012436:S-Adenosylmethionine; D008716:Methionine Adenosyltransferase; D014357:Trypsin