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令人信服的证据强烈表明，食用蔬菜和水果可能通过诱导参与致癌代谢的酶来预防癌症。虽然机制尚不完全清楚，但通过诱导谷胱甘肽s -转移酶（GST）和NAD(P)H：醌还原酶（QR）等ii期解毒酶来增强致癌亲电试剂的解毒作用似乎是该机制中最重要的一个组成部分。众所周知，gst能够代谢多种致癌物，从而将DNA损伤的风险降至最低。通过氧化还原循环，QR介导醌的双电子还原，形成相对稳定的对苯二酚，从而防止醌介导的致癌作用。已观察到抗癌物质与其诱导GST和QR活性的能力之间存在正相关关系；最近，GST活性降低与某些癌症风险增加之间的联系已被确立。这些研究激发了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，香芹和其他植物和蔬菜中的活性成分肉豆蔻素可以诱导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GSTs的诱导及其分布在不同性别和菌株的组织中并不均匀，并且已知特定的GSTs对致癌物表现出优先的代谢活性，因此将根据致癌物底物确定来自动物组织的肉豆素诱导的GSTs同工酶的功能特征。肉豆蔻素的化学预防作用将通过体内和体外模型建立。该结果有望帮助我们了解肉豆蔻素对ii期酶的诱导作用及其在开发癌症化学预防的药理学上有效的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.