PT  - JOURNAL ARTICLE
AU  - Carlson, T J
AU  - Jones, J P
AU  - Peterson, L
AU  - Castagnoli, N
AU  - Iyer, K R
AU  - Trager, W F
TI  - Stereoselectivity and isotope effects associated with cytochrome P450-catalyzed oxidation of (S)-nicotine. The possibility of initial hydrogen atom abstraction in the formation of the delta 1', 5-nicotinium ion.
DP  - 1995 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 749--756
VI  - 23
IP  - 7
4099  - http://dmd.aspetjournals.org/content/23/7/749.short
4100  - http://dmd.aspetjournals.org/content/23/7/749.full
SO  - Drug Metab Dispos1995 Jul 01; 23
AB  - The stereochemical course of cytochromes P450 [P4501A1, P4502B1, P4502B4, and P450101 (P450cam)] catalyzed alpha-carbon oxidations of the cis-(Z)- and trans-(E)-5'-d1 diastereomers of (S)-nicotine has been examined. All enzyme preparations led to the stereoselective abstraction of the 5'-hydrogen atom trans to the pyridine ring with P450101 and human liver microsomal preparations displaying the highest (90%) and P4502B1 the lowest (67%) degree of stereoselectivity. No isotope effect was detected for any of the enzyme-catalyzed reactions, although the existence of an intrinsic isotope effect was inferred by the observation of an intramolecular isotope effect of 2-2.6 observed for the N-demethylation of (S)-N'-dideuteromethylnornicotine. Evidence for P450101-catalyzed N'-oxidation was sought but could not be found at higher than trace levels. These results, together with those obtained by computational methods, are interpreted in terms of an alpha-carbon oxidative pathway involving hydrogen atom abstraction rather than single electron transfer as the initiating event in the P450-catalyzed oxidation of (S)-nicotine to its delta 1',5'-iminium ion metabolite.