Boonruang Supattra, Prakobsri Khanistha, Pouyfung Phisit, Srisook Ekaruth, Prasopthum Aruna, Rongnoparut Pornpimol, Sarapusit Songklod
a Bioengineering Program, Faculty of Engineering , Burapha University , Muang , Chonburi , Thailand.
b Department of Biochemistry, Faculty of Science , Mahidol University , Ratchathewi , Bangkok , Thailand.
J Enzyme Inhib Med Chem. 2017 Dec;32(1):1136-1142. doi: 10.1080/14756366.2017.1363741.
The human liver cytochrome P450 (CYP) 2A6 and the respiratory CYP2A13 enzymes play role in nicotine metabolism and activation of tobacco-specific nitrosamine carcinogens. Inhibition of both enzymes could offer a strategy for smoking abstinence and decreased risks of respiratory diseases and lung cancer. In this study, activity-guided isolation identified four flavonoids 1-4 (apigenin, luteolin, chrysoeriol, quercetin) from Vernonia cinerea and Pluchea indica, four hirsutinolide-type sesquiterpene lactones 5-8 from V. cinerea, and acetylenic thiophenes 9-11 from P. indica that inhibited CYP2A6- and CYP2A13-mediated coumarin 7-hydroxylation. Flavonoids were most effective in inhibition against CYP2A6 and CYP2A13, followed by thiophenes, and hirsutinolides. Hirsutinolides and thiophenes exhibited mechanism-based inhibition and in irreversible mode against both enzymes. The inactivation kinetic K values of hirsutinolides against CYP2A6 and CYP2A13 were 5.32-15.4 and 0.92-8.67 µM, respectively, while those of thiophenes were 0.11-1.01 and 0.67-0.97 µM, respectively.
人类肝脏细胞色素P450（CYP）2A6和呼吸道CYP2A13酶在尼古丁代谢以及烟草特有亚硝胺致癌物的激活过程中发挥作用。抑制这两种酶可能为戒烟以及降低呼吸道疾病和肺癌风险提供一种策略。在本研究中，活性导向分离从灰叶斑鸠菊和阔苞菊中鉴定出4种黄酮类化合物1 - 4（芹菜素、木犀草素、 Chrysoeriol、槲皮素），从灰叶斑鸠菊中鉴定出4种hirsutinolide型倍半萜内酯5 - 8，从阔苞菊中鉴定出炔基噻吩9 - 11，它们可抑制CYP2A6和CYP2A13介导的香豆素7 - 羟基化。黄酮类化合物对CYP2A6和CYP2A13的抑制作用最为有效，其次是噻吩类，然后是hirsutinolides。Hirsutinolides和噻吩类化合物对这两种酶均表现出基于机制的抑制作用且为不可逆模式。Hirsutinolides对CYP2A6和CYP2A13的失活动力学K值分别为5.32 - 15.4和0.92 - 8.67 μM，而噻吩类的K值分别为0.11 - 1.01和0.67 - 0.97 μM。
