Bennion Brian J, Cosman Monique, Lightstone Felice C, Knize Mark G, Montgomery Jennifer L, Bennett L Michelle, Felton James S, Kulp Kristen S
Biosciences Directorate, Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94551, USA.
Chem Res Toxicol. 2005 Oct;18(10):1528-36. doi: 10.1021/tx0501031.
Many carcinogens have been shown to cause tissue specific tumors in animal models. The mechanism for this specificity has not been fully elucidated and is usually attributed to differences in organ metabolism. For heterocyclic amines, potent carcinogens that are formed in well-done meat, the ability to either bind to the estrogen receptor and activate or inhibit an estrogenic response will have a major impact on carcinogenicity. Here, we describe our work with the human estrogen receptor alpha (ERalpha), the mutagenic/carcinogenic heterocyclic amines PhIP, MeIQx, and IFP, and the hydroxylated metabolite of PhIP, N2-hydroxy-PhIP. We demonstrate both by computational docking and NMR analysis that PhIP binds with the ligand binding domain (LBD). This binding competes with estradiol (E2) in the native E2 binding cavity of the receptor. In vitro assays show that PhIP, in contrast to the other heterocyclic amines, increases cell proliferation in MCF-7 human breast cancer cells and activates the ERalpha receptor. We also find that other heterocyclic amines and N2-hydroxy-PhIP inhibit ERalpha activation. We propose that the mechanism for the tissue-specific carcinogenicity seen in the rat breast tumors and the presumptive human breast cancer associated with the consumption of well-done meat maybe mediated by this receptor activation.
许多致癌物已被证明能在动物模型中引发组织特异性肿瘤。这种特异性的机制尚未完全阐明，通常归因于器官代谢的差异。对于杂环胺，即在熟透肉类中形成的强效致癌物，其与雌激素受体结合并激活或抑制雌激素反应的能力将对致癌性产生重大影响。在此，我们描述了我们对人雌激素受体α（ERα）、诱变/致癌杂环胺PhIP、MeIQx和IFP以及PhIP的羟基化代谢物N2-羟基-PhIP的研究工作。我们通过计算对接和核磁共振分析证明，PhIP与配体结合结构域（LBD）结合。这种结合在受体的天然E2结合腔中与雌二醇（E2）竞争。体外试验表明，与其他杂环胺不同，PhIP能增加MCF-7人乳腺癌细胞的增殖并激活ERα受体。我们还发现其他杂环胺和N2-羟基-PhIP抑制ERα激活。我们提出，在大鼠乳腺肿瘤以及与食用熟透肉类相关的推测性人类乳腺癌中观察到的组织特异性致癌机制可能是由这种受体激活介导的。
