Stereoselectivity in the N'-oxidation of nicotine isomers by flavin-containing monooxygenase.
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.
Damani
L A
LA
College of Pharmacy, University of Kentucky, Lexington 40536.
Pool
W F
WF
Crooks
P A
PA
Kaderlik
R K
RK
Ziegler
D M
DM
D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D009538:Nicotine / Q000378:metabolism*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D009538:Nicotine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)