Stereochemical studies on the cytochrome P-450 catalyzed oxidation of (S)-nicotine to the (S)-nicotine delta 1'(5')-iminium species.
Mammals metabolize the tobacco alkaloid (S)-nicotine primarily to the lactam (S)-cotinine by a pathway involving an initial cytochrome P-450 catalyzed two-electron oxidation at the prochiral 5'-carbon atom. The stereochemical course of this oxidation was examined with human microsomal preparations and the E and Z diastereomers of (S)-nicotine-5'd1. The metabolically generated delta 1'(5')-iminium ion intermediate was trapped and analyzed as the corresponding diastereomeric 5'-cyano derivatives by a capillary column GC-EIMS selected ion monitoring assay. The results of these studies established that this biotransformation proceeds with the stereoselective abstraction of the 5'-pro-E proton, that is, the C-5' proton trans to the bulky pyridyl group. The observed stereoselectivity was independent of proton vs. deuteron abstraction. Additionally, the extent of (S)-cotinine formation was minor and did not influence the stereochemical composition of the metabolically derived alpha-cyano amines. Studies with male Dutch rabbit liver microsomal preparations gave similar results. These findings suggest that the structure of the complex formed between (S)-nicotine and the active site of cytochrome P-450 is highly ordered and dictates the stereochemical course of the reaction pathway.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003903:Deuterium; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000378:metabolism*; D009538:Nicotine / Q000031:analogs & derivatives / Q000378:metabolism*; D011817:Rabbits; D013329:Structure-Activity Relationship
D009538:Nicotine; D003577:Cytochrome P-450 Enzyme System; D003903:Deuterium