Inhibition and inactivation of cytochrome P450 2A6 and cytochrome P450 2A13 by menthofuran, 尾-nicotyrine and menthol

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• 作者：Valerie M. Kramlinger ; Linda B. von Weymarn ; Sharon E. Murphy ; ^{murph062@umn.edu}
• 关键词：Menthol ; (&minus ; )-menthol or (1R ; 2S ; 5R)-2-isopropyl-5-methylcyclohexanol ; Menthofuran ; (R)-(+)-menthofuran or 3 ; 6R-dimethyl-4 ; 5 ; 6 ; 7-tetrahydro-1-benzofuran ; NNK ; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone ; 尾-Nicotyrine ; 1-methyl-4-(3-pyridinyl) pyrr
• 刊名：Chemico-Biological Interactions
• 出版年：2012
• 期刊代码：6_00092797
• 类别：pha
• 出版时间：30 May, 2012
• 卷：197
• 期：2-3
• 页码：87-92
• 文件大小：241 K

摘要

Nicotine is the primary addictive agent in tobacco products and is metabolized in humans by CYP2A6. Decreased CYP2A6 activity has been associated with decreased smoking. The extrahepatic enzyme, CYP2A13 (94%identical to CYP2A6) also catalyzes the metabolism of nicotine, but is most noted for its role in the metabolic activation of the tobacco specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this study, the inhibition and potential inactivation of CYP2A6 and CYP2A13 by two tobacco constituents, 1-methyl-4-(3-pyridinyl) pyrrole (尾-nicotyrine) and (鈭?-menthol were characterized and compared to the potent mechanism based inactivator of CYP2A6, menthofuran. The effect of these compounds on CYP2A6 and CYP2A13 activity was significantly different. (-)-Menthol was a more efficient inhibitor of CYP2A13 than of CYP2A6 (K_I, 8.2 渭M and 110 渭M, respectively). 尾-Nicotyrine was a potent inhibitor of CYP2A13 (K_I, 0.17 渭M). Neither menthol nor 尾-nicotyrine was an inactivator of CYP2A13. Whereas, 尾-nicotyrine was a mechanism based inactivator of CYP2A6 (K_I(inact), 106 渭M, k_inact was 0.61 min^鈭?). Similarly, menthofuran, a potent mechanism based inactivator of CYP2A6 did not inactivate CYP2A13. Menthofuran was an inhibitor of CYPA13 (K_I, 1.24 渭M). The inactivation of CYP2A6 by either 尾-nicotyrine or menthofuran was not due to modification of the heme and was likely due to modification of the apo-protein. These studies suggest that 尾-nicotyrine, but not menthol may influence nicotine and NNK metabolism in smokers.