Diastereospecific kinetics of nicotine N'-oxidation in rat liver microsomes.
1. In kinetic studies, both Eadie-Hofstee plots for cis- and trans-nicotine-1'-N-oxide formation from nicotine in rat liver microsomes were linear. For the formation of cis- and trans-nicotine-1'-N-oxide, the apparent K(m) were 0.240 +/- 0.069 and 1.524 +/- 0.951 mM respectively. Corresponding Vmax were 1.52 +/- 0.48 and 1.19 +/- 0.74 nmol/mg/min respectively. 2. The formation of cis-nicotine-1'-N-oxide was greater than the formation of trans-nicotine-1'-N-oxide in rat liver microsomes and the intrinsic clearance of cis-nicotine-1'-N-oxide formation was 8.1-fold greater than that of trans-nicotine-1'-N-oxide formation. 3. The formation of both cis- and trans-nicotine-1'-N-oxide in rat liver microsomes was inhibited by the addition of 1-(1-naphthyl)-2-thiourea or by heat-treatment of microsomes. 2-Diethylaminoethyl-2, 2-diphenylvalerate (SKF525A) and carbon monoxide did not affect these activities even at high concentrations. 4. Formations of cis- and trans-nicotine-1'-N-oxide correlated significantly with each other (r = 0.862, p < 0.01). These results suggested that the same flavin-containing monooxygenase (FMO) isoform is responsible for the formation of cis- and trans-nicotine-1'-N-oxide in rat liver.
Nakajima
M
M
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Iwata
K
K
Yoshida
T
T
Yamamoto
T
T
Kuroiwa
Y
Y
D000818:Animals; D003497:Cyclic N-Oxides / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004795:Enzyme Stability; D005420:Flavoproteins / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000502:physiology*; D008968:Molecular Conformation; D009538:Nicotine / Q000031:analogs & derivatives* / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D003497:Cyclic N-Oxides; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005420:Flavoproteins; C024270:nicotine 1-N-oxide; D009538:Nicotine; D013890:Thiourea