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Drug Metab Dispos

Title:		Metabolism-based inactivation of neuronal nitric-oxide synthase by components of cigarette and cigarette smoke
Author(s):		Demady DR; Lowe ER; Everett AC; Billecke SS; Kamada Y; Dunbar AY; Osawa Y;
Address:		"Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA"
Journal Title:		Drug Metab Dispos
Year:		2003
Volume:		31
Issue:		7
Page Number:		932 - 937
DOI:		10.1124/dmd.31.7.932
ISSN/ISBN:		0090-9556 (Print) 0090-9556 (Linking)
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"
Keywords:		Arginine/*analogs & derivatives/metabolism Calmodulin/metabolism Enzyme Inhibitors/metabolism NADP/metabolism Nitric Oxide Synthase/*antagonists & inhibitors/drug effects/*metabolism Nitric Oxide Synthase Type I Nitric Oxide Synthase Type III Smoke/*analy;
Notes:		"MedlineDemady, Damon R Lowe, Ezra R Everett, Andrew C Billecke, Scott S Kamada, Yasuhiko Dunbar, Anwar Y Osawa, Yoichi eng GM07767/GM/NIGMS NIH HHS/ Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. 2003/06/20 Drug Metab Dispos. 2003 Jul; 31(7):932-7. doi: 10.1124/dmd.31.7.932"