在癌症治疗和预防方面的饮食黄酮类化合物︰细胞色素 P450 CYP1 酶的基质和抑制剂_迪米崔欧斯

针对病种：癌症

发表时间：2010年4月

发表国家：英国

登载刊物：药理学与治疗学

研究单位：希腊克里特岛大学法医和毒理学实验室

研究人员：迪米崔欧斯 A 斯班迪德斯等

主要结论：黄酮类化合物是多酚类化合物，作为标志分子通过大量不同机制预防癌症，吸引了科学界的注意。他们最重要特征之一，决定其癌症预防性质，是它们与细胞色素 P450 CYP1 酶的相互作用。黄酮类化合物传统上被描述为 CYP1的抑制剂，由于其抑制致癌产物形成和堵塞癌变启动阶段的作用。然而，越来越多的证据表明，黄酮类化合物也能够作为 CYP1 的基底，承受更多抗增殖剂在肿瘤细胞内的生物激活.

Pharmacology & Therapeutics, 2010, 126(1):9-20.

Dietary flavonoids in cancer therapy and prevention: Substrates and inhibitors of cytochrome P450 CYP1 enzymes

Demetrios A. Spandidos, et al

Laboratory of Forensic Sciences and Toxicology, University of Crete, Heraklion, Voutes, 71003, Greece

Flavonoids are polyphenolic compounds that have attracted the attention of the scientific community as the hallmark molecules responsible for cancer prevention by a plethora of different mechanisms. One of their most important characteristics, responsible for their cancer preventive properties, is their interaction with cytochrome P450 CYP1 enzymes. Flavonoids have traditionally been described as CYP1 inhibitors due to the inhibition of carcinogenic product formation and consequent blockage of the initiation stage of carcinogenesis. However, mounting evidence indicate that flavonoids are also capable of acting as CYP1 substrates, undergoing bioactivation to more antiproliferative agents within cancer cells. In this review, a comprehensive summary of the two models is presented. Structural features responsible for CYP1 inhibition or substrate turnover are discussed and limitations as well as discrepancies between procarcinogen-activating and 7-ethoxyresorufin-inhibition assay systems are further explored in vitro and in vivo. Moreover, a thorough investigation of the substrate specificity of flavonoids for the active site of CYP1 enzymes is undertaken. Finally, issues concerning the bioavailability and metabolic fate of these compounds in vivo are addressed. Ultimately, the mode of flavonoid action, in terms of CYP1 inhibition or CYP1-mediated bioactivation, is dependent on the lipophilicity or hydrophilicity of each compound. The degree of hydroxylation or methoxylation of the A and B rings is the major factor which determines the accessibility to the tumor site, in terms of hepatic and intestinal metabolism, and the introduction of the molecules to the CYP1 active site, respectively.

英国《药理学与治疗学》，2010年4月

在癌症治疗和预防方面的饮食黄酮类化合物︰细胞色素 P450 CYP1 酶的基质和抑制剂

迪米崔欧斯 A 斯班迪德斯等

希腊克里特岛大学法医和毒理学实验室

黄酮类化合物是多酚类化合物，作为标志分子通过大量不同机制预防癌症，吸引了科学界的注意。他们最重要特征之一，决定其癌症预防性质，是它们与细胞色素 P450 CYP1 酶的相互作用。黄酮类化合物传统上被描述为 CYP1的抑制剂，由于其抑制致癌产物形成和堵塞癌变启动阶段的作用。然而，越来越多的证据表明，黄酮类化合物也能够作为 CYP1 的基底，承受更多抗增殖剂在肿瘤细胞内的生物激活。在这篇综述中，提出了两种模型的综合概要。讨论了用于CYP1 抑制或基底周转的结构特点和局限性，以及进一步探索体外和体内原致癌原激活和 7-乙氧基异吩恶唑-抑制鉴定体系之间的差异。此外，开展了对黄酮类化合物作为CYP1 酶活性部位的底物特异性的彻底调查。最后，解决了有关这些化合物在体内的生物利用度和代谢率的问题。最终，黄酮类化合物关于CYP1 抑制或 CYP1 介导的生物活性的作用模式，是依赖于每种化合物的亲油性或亲水性。代表了羟化反应或甲氧基化程度的圈 A 和圈B 是确定能否到达肿瘤部位的主要因素，分别表示了肝脏和肠道代谢以及被引入到CYP1 活性部位中的分子。