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Research ArticleArticle

METABOLISM-BASED INACTIVATION OF NEURONAL NITRIC-OXIDE SYNTHASE BY COMPONENTS OF CIGARETTE AND CIGARETTE SMOKE

Damon R. Demady, Ezra R. Lowe, Andrew C. Everett, Scott S. Billecke, Yasuhiko Kamada, Anwar Y. Dunbar and Yoichi Osawa
Drug Metabolism and Disposition July 2003, 31 (7) 932-937; DOI: https://doi.org/10.1124/dmd.31.7.932
Damon R. Demady
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Ezra R. Lowe
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Andrew C. Everett
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Scott S. Billecke
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Yasuhiko Kamada
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Anwar Y. Dunbar
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Yoichi Osawa
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Abstract

It has been shown that administration of cigarette smoke to rats leads to loss of neuronal nitric-oxide synthase (nNOS) activity and nNOS protein in penile tissue. The exact mechanism for this loss of activity and protein is not known. In the current study, we investigated whether extracts prepared from cigarette smoke or from the cigarette itself could directly inhibit nNOS activity. We discovered that the cigarette smoke extract and the cigarette extract cause a time-, concentration-, and calmodulin-dependent inactivation of nNOS in an in vitro system containing the purified enzyme. L-Arginine, but not D-arginine, protects nNOS from this time-dependent inactivation, suggesting an active site directed event. The kinetics of inactivation are consistent with the metabolism-based or suicide inactivation of nNOS. Based on studies with other metabolism-based inactivators, this cigarette-mediated inactivation may render nNOS more susceptible to proteasomal degradation and thereby may explain the loss of nNOS protein in vivo. The component(s) responsible for nNOS inactivation is not volatile, is not retained by a 3,000 molecular weight cut-off membrane, binds to activated charcoal, and is highly water-soluble under both acidic and basic conditions. The discovery of a direct inactivation of nNOS by an organic, cationic compound(s) present in tobacco and tobacco smoke provides a basis for further study of not only the mechanisms responsible for the biological effects of tobacco but also a search for a potentially novel inactivator of nNOS.

Footnotes

  • ↵1 These authors are both considered first authors.

  • ↵2 Trainee under Pharmacological Sciences Training Program GM07767 from the National Institutes of Health.

  • ↵3 Abbreviations used are: NO, nitric oxide; NOS, nitric-oxide synthase; nNOS, neuronal NOS; eNOS, endothelial NOS; BH4, (6R)-5,6,7,8-tetrahydro-l-biopterin; CSE, the water extract made from cigarette smoke; CE, the water extract made directly from the nonburned cigarette; CAM, calmodulin; ASE, Accord smoke extracts; LSE, Lattuca sativa smoke extracts; ADMA, asymmetric dimethyl-l-arginine.

  • Supported in part by the Philip Morris External Research Program.

    • Received January 24, 2003.
    • Accepted April 9, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (7)
Drug Metabolism and Disposition
Vol. 31, Issue 7
1 Jul 2003
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Research ArticleArticle

METABOLISM-BASED INACTIVATION OF NEURONAL NITRIC-OXIDE SYNTHASE BY COMPONENTS OF CIGARETTE AND CIGARETTE SMOKE

Damon R. Demady, Ezra R. Lowe, Andrew C. Everett, Scott S. Billecke, Yasuhiko Kamada, Anwar Y. Dunbar and Yoichi Osawa
Drug Metabolism and Disposition July 1, 2003, 31 (7) 932-937; DOI: https://doi.org/10.1124/dmd.31.7.932

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Research ArticleArticle

METABOLISM-BASED INACTIVATION OF NEURONAL NITRIC-OXIDE SYNTHASE BY COMPONENTS OF CIGARETTE AND CIGARETTE SMOKE

Damon R. Demady, Ezra R. Lowe, Andrew C. Everett, Scott S. Billecke, Yasuhiko Kamada, Anwar Y. Dunbar and Yoichi Osawa
Drug Metabolism and Disposition July 1, 2003, 31 (7) 932-937; DOI: https://doi.org/10.1124/dmd.31.7.932
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