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Stereoselectivity in the N'-oxidation of nicotine isomers by flavin- containing monooxygenase

LA Damani, WF Pool, PA Crooks, RK Kaderlik and DM Ziegler

College of Pharmacy, University of Kentucky, Lexington 40536.

N'-Oxidation of nicotine isomers by porcine liver flavin-containing monooxygenase shows a clear stereoselectivity in the formation of the diastereomeric N'-oxides. (S)-(-)-Nicotine exhibited no stereoselectivity in the formation of cis-1'R,2'S- and trans-1'S,2'S- products, whereas with (R)-(+)-nicotine, only the trans-1'R,2'R-N'- oxide was formed. The concentration of each isomer required for half maximal activity differs significantly, and access of (S)-(-)-nicotine to the active site appears to be more restricted than for (R)-(+)- nicotine as judged from the observed Km values (Km = 181 and 70 microM, respectively, for the (S)-(-)- and (R)-(+)-isomers). These results indicate that a region adjacent to the active site may sterically prohibit binding of (R)-(+)-nicotine when the N'-methyl and pyridyl groups are in a cis-orientation. N-Methylnicotinium ion (both R- and S- isomers) is not a substrate for either porcine flavin monooxygenase, guinea pig liver microsomes, or ram seminal vesicular microsomes.

Volume 33, Issue 6, pp. 702-705, 06/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics




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