Mechanism of Anticarcinigenic Effects of Myristicin

描述(由申请人提供)：通过流行病学研究和实验调查积累的大量令人信服的证据有力地表明，食用蔬菜和水果可能通过诱导参与致癌新陈代谢的酶来预防癌症。虽然机制还不完全清楚，但通过诱导谷胱甘肽S转移酶和NAD(P)H：苯醌还原酶(QR)等第二相解毒酶来增强致癌亲电体的解毒似乎是该机制中最重要的组成部分。已知GST可代谢多种致癌物质，从而将DNA损伤的风险降至最低。通过氧化还原循环，QR介导了对苯二酚的两电子还原反应，形成了相对稳定的对苯二酚，从而防止了对苯二酚的致癌作用。已经观察到抗癌物质与它们诱导GST和QR活性的能力之间的正相关；最近，GST活性降低与某些癌症风险增加之间的关联已被确立。这些研究激发了人们对能够诱导解毒酶的天然植物化学物质的研究。我们的研究和其他研究表明，肉豆蔻素是欧芹和其他植物和蔬菜的活性成分，可以诱导GST活性并抑制小鼠组织中的肿瘤发生，因此似乎是一种潜在的化学保护剂。由于肉豆蔻菌素诱导的GSTs在不同性别和菌株的组织中的分布并不一致，而且已知特定的GSTs对致癌物质具有优先代谢活性，因此将针对致癌底物确定肉豆蔻菌素诱导的动物组织GSTs同工酶的功能特征。肉豆蔻菌素的化学预防效果将通过体内和体外模型来建立。这些结果有望帮助我们理解肉豆蔻菌素诱导的II相酶及其在开发药理上有效的癌症化学预防饮食策略方面的潜力。

DESCRIPTION (provided by applicant): A compelling body of evidence accumulated through epidemiologic studies and experimental investigations strongly suggest that consumption of vegetables and fruits provide protection against cancer presumably by induction of enzymes that are involved in carcinogenic metabolism. Although the mechanism is not entirely understood, enhancement of detoxification of carcinogenic electrophiles by inducing Phase-II detoxification enzymes such as glutathione S-transferase (GST) and NAD(P)H: quinone reductase (QR) appears to be the single most important component of the mechanisms. GSTs are known to metabolize a number of carcinogens thus minimizing the risk of DNA damage. Through redox cycling, QR mediates the two-electron reduction of quinones leading to the formation of relatively stable hydroquinones, thereby protecting against quinonide-mediated carcinogenesis. A positive correlation between the anticarcinogens, and their ability to induce GST and QR activities, has been observed; more recently an association between decreased GST activity and increased risk of certain cancers has been established. These studies have inspired the search of naturally occurring phytochemicals capable of inducing detoxification enzymes. Our studies and others show that Myristicin, an active constituent of parsley and other plants and vegetables, induces GST activity and inhibits tumorigenesis in mouse tissues and thus appears to be a potential chemoprotective agent. Since induction of GSTs, like their distribution, is not uniform among tissues of different gender and strains, and that specific GSTs are known to exhibit preferential metabolic activity towards carcinogens, the functional characteristics of myristicin induced GSTs isoenzymes from tissues of animals will be determined against carcinogenic substrates. The chemopreventive efficacy of myristicin will be established using in vivo and in vitro models. The results are expected to help us understand the Phase-II enzyme induction by myristicin and its potential in developing pharmacologically effective dietary strategies for cancer chemoprevention.