Characterization of b-nicotyrine-mediated inactivation of cytochrome P450 2A6
2013-04
Title
Characterization of b-nicotyrine-mediated inactivation of cytochrome P450 2A6
Authors
Published Date
2013-04
Publisher
Type
Thesis or Dissertation
Abstract
Nicotine, the primary addictive compound in cigarettes, is metabolized in humans by cytochrome P450 2A enzymes. The hepatic enzyme responsible for the metabolism of nicotine in smokers is P450 2A6. P450 2A13, which shares 94% primary sequence homology with P450 2A6, also catalyzes the metabolism of nicotine and is present in the lung. Loss of P450 2A activity is correlated with modified smoking behavior and addiction. Inhibition of these enzymes decreases nicotine metabolism and may be of benefit in smoking cessation. This thesis investigates tobacco-related molecules that may impact P450 2A function and is presented in three parts. In the first, the potential inhibitory potency of (-)-menthol, (R)-(+)-menthofuran, and -nicotyrine of both P450s 2A6 and 2A13 are investigated. All three compounds inhibit P450 2A6 and 2A13 activity. In addition, menthofuran and b-nicotyrine mediate mechanism-based inactivation of P450 2A6 but not 2A13. Second, the P450 2A6 and P450 2A13-mediated metabolism of b-nicotyrine is studied and three metabolites are identified. b-nicotyrine is readily turned over by both P450 2A6 and P450 2A13 as indicated by the calculated Km (4.4µM and 5.0µM, respectively) and Vmax (21 and 37 pmol product/min/pmol, respectively) values. Also in the second section, b-nicotyrine is shown to be a metabolite of P450 2A6-mediated nicotine metabolism. In the last section, attempts to identify a covalent adduct that would result from menthofuran or b-nicotyrine-mediated inactivation are presented, but these are largely unsuccessful.
Keywords
Description
University of Minnesota Ph.D. dissertation. April 2013. Major: Biochemistry, Molecular Bio, and Biophysics. Advisor: Sharon E. Murphy. 1 computer file (PDF); vii, 109 pages.
Related to
Replaces
License
Collections
Series/Report Number
Funding information
Isbn identifier
Doi identifier
Previously Published Citation
Suggested citation
Kramlinger, Valerie Marie. (2013). Characterization of b-nicotyrine-mediated inactivation of cytochrome P450 2A6. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/163248.
Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.