Transient induction of cytochromes P450 1A1 and 1B1 in MCF-7 human breast cancer cells by indirubin.
Transient induction of cytochromes P450 1A1 and 1B1 in MCF-7 human breast cancer cells by indirubin.
复制标题
DOI：
10.1016/j.bcp.2003.08.019
复制
发表时间：
2003-12
影响因子：
5.8
通讯作者：
B. C. Spink;M. Hussain;B. H. Katz;L. Eisele;D. Spink
中科院分区：
文献类型：
--
作者：
B. C. Spink;M. Hussain;B. H. Katz;L. Eisele;D. Spink
芳香烃受体(AhR)被2，3，7，8-四氯二苯并-对二恶英(TCDD)等外源配体激活后，可调节多种I相酶和II相酶的表达，并参与细胞增殖的调控。多项研究表明，可能存在内源性AhR配体(S)。一种可能的内源性配体是靛玉红，最近在人尿和牛血清中发现了它。通过雌二醇和乙氧基间苯二酚代谢测定，我们确定了在MCF-7乳腺癌细胞中，靛玉红对细胞色素P450(CYP)1A1和1B1活性的诱导以及对细胞色素P450(CYP)1A1和1B1mRNAs的诱导。与TCDD不同，在4小时的照射下，10 nm波长的吲哚红和TCDD对细胞色素P450活性的影响是相似的，但与TCDD不同，靛玉红的作用是短暂的。蓝宝石诱导的乙氧基间苯二酚-O-脱乙基酶活性在暴露后6-9小时达到最大值，24小时后消失，而TCDD诱导的活性至少在72小时内保持高水平。吲哚红对CYP mRNA的诱导作用在3hr时达到最大。含表达人细胞色素P1A1或细胞色素P1B1基因的微粒体能代谢吲哚红。在CYP1B1启动子驱动的荧光素酶实验中，当AhR配体和Cyp抑制剂椭圆碱共同作用于MCF-7细胞时，靛玉红的效力与TCDD相当。因此，如果蓝宝石是一种内源性AhR配体，那么蓝宝石介导的AhR信号很可能是短暂的，并受到其诱导细胞色素P1A1和细胞色素P1B1的能力的严格控制，从而导致其自身的代谢。
The aryl hydrocarbon receptor (AhR), when activated by exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), regulates expression of several phase I and phase II enzymes and is also involved in the regulation of cell proliferation. Several studies suggest that endogenous AhR ligand(s) may exist. One putative endogenous ligand is indirubin, which was recently identified in human urine and bovine serum. We determined the effect of indirubin in MCF-7 breast cancer cells on induction of the activities of cytochromes P450 (CYP) 1A1 and 1B1, as measured by estradiol and ethoxyresorufin metabolism, and on induction of the CYP1A1 and CYP1B1 mRNAs. With 4-hr exposure, the effects of indirubin and TCDD at 10nM on CYP activity were comparable, but the effects of indirubin, unlike those of TCDD, were transitory. Indirubin-induced ethoxyresorufin-O-deethylase activity was maximal by 6–9hr post-exposure and had disappeared by 24hr, whereas TCDD-induced activities remained elevated for at least 72hr. The effects of indirubin on CYP mRNA induction were maximal at 3hr. Indirubin was metabolized by microsomes containing cDNA-expressed human CYP1A1 or CYP1B1. The potency of indirubin was comparable to that of TCDD in a CYP1B1-promoter-driven luciferase assay, when MCF-7 cells were co-exposed to the AhR ligands together with the CYP inhibitor, ellipticine. Thus, if indirubin is an endogenous AhR ligand, then AhR-mediated signaling by indirubin is likely to be transient and tightly controlled by the ability of indirubin to induce CYP1A1 and CYP1B1, and hence its own metabolism.