Mechanism and tissue specificity of nicotine-mediated lung S-adenosylmethionine reduction.
We previously reported that chronic nicotine infusion blocks development of Pneumocystis pneumonia. This discovery developed from our work demonstrating the inability of this fungal pathogen to synthesize the critical metabolic intermediate S-adenosylmethionine and work by others showing nicotine to cause lung-specific reduction of S-adenosylmethionine in guinea pigs. We had found nicotine infusion to cause increased lung ornithine decarboxylase activity (rate-controlling enzyme of polyamine synthesis) and hypothesized that S-adenosylmethionine reduction is driven by up-regulated polyamine biosynthesis. Here we report a critical test of our hypothesis; inhibition of ornithine decarboxylase blocks the effect of nicotine on lung S-adenosylmethionine. Further support is provided by metabolite analyses showing nicotine to cause a strong diversion of S-adenosylmethionine toward polyamine synthesis and away from methylation reactions; these shifts are reversed by inhibition of ornithine decarboxylase. Because the nicotine effect on Pneumocystis is so striking, we considered the possibility of tissue specificity. Using laser capture microdissection, we collected samples of lung alveolar regions (site of infection) and respiratory epithelium for controls. We found nicotine to cause increased ornithine decarboxylase protein in alveolar regions but not airway epithelium; we conclude that tissue specificity likely contributes to the effect of nicotine on Pneumocystis pneumonia. Earlier we reported that the full effect of nicotine requires 3 weeks of treatment, and here we show recovery is symmetrical, also requiring 3 weeks after treatment cessation. Because this time frame is similar to pneumocyte turnover time, the shift in polyamine metabolism may occur as new pneumocytes are produced.
Moncada
Camilo A
CA
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Clarkson
Allen
A
Perez-Leal
Oscar
O
Merali
Salim
S
D000818:Animals; D015317:Biogenic Polyamines / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006168:Guinea Pigs; D042282:Microdissection; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009928:Organ Specificity / Q000187:drug effects; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D010084:Oxidation-Reduction / Q000187:drug effects; D011010:Pneumocystis; D011020:Pneumonia, Pneumocystis / Q000201:enzymology* / Q000473:pathology; D011650:Pulmonary Alveoli / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000201:enzymology; D012436:S-Adenosylmethionine / Q000378:metabolism*; D013997:Time Factors
D015317:Biogenic Polyamines; D018722:Nicotinic Agonists; D009538:Nicotine; D012436:S-Adenosylmethionine; D009955:Ornithine Decarboxylase