PDF(Pubmed)
Abstract：
As a potential means for smoking cessation and consequently prevention of smoking-related diseases and mortality, in this study, our goal was to investigate the inhibition of nicotine metabolism by P450 2A6. Smoking is the main cause of many diseases and disabilities and harms nearly every organ of the body. As reported by the Centers for Disease Control and Prevention (CDC), more than 16 million Americans are living with diseases caused by smoking. On average, the life expectancy of a smoker is about 10 years less than a nonsmoker. Smoking cessation can substantially reduce the incidence of smoking-related diseases, including cancer. At least, 70 of the more than 7000 cigarette smoke components, including polycyclic aromatic hydrocarbons, N-nitrosamines, and aromatic amines, are known carcinogens. Nicotine is the compound responsible for the addictive and psychopharmacological effects of tobacco. Cytochrome P450 enzymes are responsible for the phase I metabolism of many tobacco components, including nicotine. Nicotine is mainly metabolized by cytochrome P450s 2A6 and 2A13 to cotinine. This metabolism decreases the amount of available nicotine in the bloodstream, leading to increased smoking behavior and thus exposure to tobacco toxicants and carcinogens. Here, we report the syntheses and P450 2A6 inhibitory activities of a number of new flavone-based esters and acids. Three of the flavone derivatives studied were found to be potent competitive inhibitors of the enzyme. Docking studies were used to determine the possible mechanisms of the activity of these inhibitors.
摘要：
作为戒烟和预防吸烟相关疾病和死亡的潜在手段，在这项研究中，我们的目的是研究P4502A6对尼古丁代谢的抑制作用。吸烟是许多疾病和残疾的主要原因，几乎危害身体的每个器官。据疾病控制和预防中心（CDC）报道，超过1600万美国人生活在吸烟引起的疾病中。平均而言,吸烟者的预期寿命比不吸烟者少10年。戒烟可以大大降低吸烟相关疾病的发病率,包括癌症.至少,7000多种香烟烟雾成分中的70种，包括多环芳烃，N-亚硝胺,和芳香胺，是已知的致癌物。尼古丁是负责烟草成瘾和精神药理学作用的化合物。细胞色素P450酶负责许多烟草成分的I期代谢，包括尼古丁。尼古丁主要由细胞色素P450s2A6和2A13代谢为可替宁。这种新陈代谢减少了血液中可用的尼古丁的量，导致吸烟行为增加，从而暴露于烟草毒物和致癌物。这里,我们报告了许多新的黄酮基酯和酸的合成和P4502A6抑制活性。发现所研究的三种黄酮衍生物是该酶的有效竞争性抑制剂。对接研究用于确定这些抑制剂活性的可能机制。
