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J. Biol. Chem., Vol. 280, Issue 15, 15219-15228, April 15, 2005

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Effect of Nicotine on Lung S-Adenosylmethionine and Development of Pneumocystis Pneumonia^*

Mehboob Shivji, Suzanna Burger, Camilo Andres Moncada, Allen B. Clarkson, Jr., and Salim Merali

From the Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, New York 10010

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 µg 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 µg 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.

Received for publication, December 10, 2004 , and in revised form, January 14, 2005.

^* This work was supported by NIH/NIAID Grants RO1A1064017 and RO1A141947. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Medical and Molecular Parasitology, NY University School of Medicine, 341 East 25th St., New York, NY. Tel.: 212-263-6956; Fax: 212-263-8116; E-mail: merals01{at}popmail.med.nyu.edu.

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This article has been cited by other articles:

				C. A. Moncada, A. Clarkson, O. Perez-leal, and S. Merali Mechanism and Tissue Specificity of Nicotine-mediated Lung S-Adenosylmethionine Reduction J. Biol. Chem., March 21, 2008; 283(12): 7690 - 7696. [Abstract] [Full Text] [PDF]

				A. K. Greenberg, B. Rimal, K. Felner, S. Zafar, J. Hung, E. Eylers, B. Phalan, M. Zhang, J. D. Goldberg, B. Crawford, et al. S-Adenosylmethionine as a Biomarker for the Early Detection of Lung Cancer Chest, October 1, 2007; 132(4): 1247 - 1252. [Abstract] [Full Text] [PDF]