Go Ryeo-Eun, Hwang Kyung-A, Choi Kyung-Chul
Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763,Republic of Korea.
Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763,Republic of Korea.
J Steroid Biochem Mol Biol. 2015 Mar;147:24-30. doi: 10.1016/j.jsbmb.2014.11.003. Epub 2014 Nov 6.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor that dimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT). This complex binds to xenobiotics response element (XREs), and then starts the expressions of downstream genes including cytochrome P450 (CYP) 1 family members: CYP1A1, CYP1A2 and CYP1B1. Role of CYP1 family is involved in the metabolism of endogenous hormones, xenobiotics and drug. The expression of CYP1 family is regulated by estradiol (E2) or xenobiotics in diverse cancers. In breast cancers expressing estrogen receptors (ERs), level of CYP1B1 is increased by E2 and reversed by an estrogen receptor antagonist, ICI 182,780 or 4-hydrotamoxifen, which indicates that the expression of CYP1 family in downstream region of AhR is regulated by an activation of ERα. In metabolic pathways, E2 is converted into 4-hydroxyestradiol by CYP1B1, which can be converted into mainly estradiol-3,4-quinone, a potential carcinogen, by peroxidase. Increased expression of CYP1 family indicates the possibility of carcinogenesis by exposure of xenobiotics in endometrial and ovarian cancers. Apart from roles of CYP1 family in relation with ER pathway, CYP1 family is over-expressed in ER independent cancers. CYP1A1 exhibits hydroxylase activity in oxidation of arachidonic acid, which has been transformed to 12(R)-hydrxyeicosatetraenoic (HETEs), a potent activator of AhR activity. On the basis of results, phytoestrogens and dexamethasone are provided as cancer therapy regulating the expression of CYP1 family. Thus, this review focuses on the role(s) of CYP1 family in ER-dependent or ER-independent cancers and the potential for cancer therapy to target CYP1 family in these cancers.
芳烃受体（AhR）是一种配体激活的转录因子，它与芳烃受体核转运蛋白（ARNT）二聚化。这种复合物与外源性物质反应元件（XREs）结合，然后启动包括细胞色素P450（CYP）1家族成员：CYP1A1、CYP1A2和CYP1B1在内的下游基因的表达。CYP1家族的作用涉及内源性激素、外源性物质和药物的代谢。CYP1家族的表达在多种癌症中受雌二醇（E2）或外源性物质的调节。在表达雌激素受体（ERs）的乳腺癌中，CYP1B1的水平因E2而升高，并被雌激素受体拮抗剂ICI 182,780或4-羟基他莫昔芬逆转，这表明AhR下游区域的CYP1家族表达受ERα激活的调节。在代谢途径中，E2被CYP1B1转化为4-羟基雌二醇，后者可被过氧化物酶主要转化为潜在致癌物雌二醇-3,4-醌。CYP1家族表达的增加表明子宫内膜癌和卵巢癌中外源性物质暴露导致致癌的可能性。除了CYP1家族与ER途径相关的作用外，CYP1家族在ER非依赖性癌症中也过度表达。CYP1A1在花生四烯酸氧化中表现出羟化酶活性，花生四烯酸已被转化为12（R）-羟基二十碳四烯酸（HETEs），一种强效的AhR活性激活剂。基于这些结果，植物雌激素和地塞米松被作为调节CYP1家族表达的癌症治疗药物。因此，本综述重点关注CYP1家族在ER依赖性或ER非依赖性癌症中的作用以及针对这些癌症中CYP1家族进行癌症治疗的潜力。
