大鼠肝脏微粒体中尼古丁N'-氧化的非对映体特异性动力学

Diastereospecific kinetics of nicotine N'-oxidation in rat liver microsomes.

Nakajima M, Iwata K, Yoshida T, Yamamoto T, Kuroiwa Y

Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.

Xenobiotica. 1998 Feb;28(2):127-35. doi: 10.1080/004982598239632.

Abstract

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.

摘要

在动力学研究中，大鼠肝微粒体中尼古丁生成顺式和反式尼古丁-1'-N-氧化物的伊迪-霍夫斯蒂图均呈线性。对于顺式和反式尼古丁-1'-N-氧化物的生成，表观K(m)分别为0.240±0.069和1.524±0.951 mM。相应的Vmax分别为1.52±0.48和1.19±0.74 nmol/mg/min。2. 在大鼠肝微粒体中，顺式尼古丁-1'-N-氧化物的生成量大于反式尼古丁-1'-N-氧化物的生成量，顺式尼古丁-1'-N-氧化物生成的内在清除率比反式尼古丁-1'-N-氧化物生成的内在清除率高8.1倍。3. 在大鼠肝微粒体中加入1-(1-萘基)-2-硫脲或对微粒体进行热处理，可抑制顺式和反式尼古丁-1'-N-氧化物的生成。即使在高浓度下，2-二乙氨基乙基-2,2-二苯基戊酸酯(SKF525A)和一氧化碳也不影响这些活性。4. 顺式和反式尼古丁-1'-N-氧化物的生成彼此显著相关(r = 0.862，p < 0.01)。这些结果表明，同一含黄素单加氧酶(FMO)同工型负责大鼠肝脏中顺式和反式尼古丁-1'-N-氧化物的生成。