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.
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.
Carlson
T J
TJ
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195, USA.
Jones
J P
JP
Peterson
L
L
Castagnoli
N
N
Iyer
K R
KR
Trager
W F
WF
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D006859:Hydrogen / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008968:Molecular Conformation; D009538:Nicotine / Q000378:metabolism*; D010084:Oxidation-Reduction; D011789:Quantum Theory; D011817:Rabbits; D051381:Rats; D013237:Stereoisomerism
D007527:Isoenzymes; D009538:Nicotine; D006859:Hydrogen; D003577:Cytochrome P-450 Enzyme System