Damani L A, Pool W F, Crooks P A, Kaderlik R K, Ziegler D M
College of Pharmacy, University of Kentucky, Lexington 40536.
Mol Pharmacol. 1988 Jun;33(6):702-5.
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.
猪肝脏含黄素单加氧酶对尼古丁异构体的N'-氧化作用在非对映体N'-氧化物的形成过程中表现出明显的立体选择性。(S)-(-)-尼古丁在顺式-1'R,2'S-和反式-1'S,2'S-产物的形成过程中未表现出立体选择性，而对于(R)-(+)-尼古丁，仅形成反式-1'R,2'R-N'-氧化物。达到最大活性一半时所需的每种异构体浓度差异显著，从观察到的Km值（(S)-(-)-和(R)-(+)-异构体的Km分别为181和70 microM）判断，(S)-(-)-尼古丁进入活性位点似乎比(R)-(+)-尼古丁更受限制。这些结果表明，当N'-甲基和吡啶基处于顺式取向时，活性位点附近的区域可能在空间上阻止(R)-(+)-尼古丁的结合。N-甲基烟碱离子（R-和S-异构体）既不是猪黄素单加氧酶、豚鼠肝脏微粒体也不是公羊精囊微粒体的底物。
