Yin Hou-Chu, Tseng Hua-Pin, Chung Hsin-Yu, Ko Chin-Yi, Tzou Wen-Shyong, Buhler Donald R, Hu Chin-Hwa
Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan, ROC.
Toxicol Sci. 2008 May;103(1):158-68. doi: 10.1093/toxsci/kfn035. Epub 2008 Feb 27.
Cytochrome P450 1B1 (CYP1B1) is a heme-containing monooxygenase that metabolizes various polycyclic aromatic hydrocarbons and aryl amines, as well as retinoic acid and steroid hormones. Here we report the cloning of an ortholog of CYP1B1 from zebrafish and the demonstration that transcription of zebrafish CYP1B1 was modulated by two types of mechanisms during different developmental stage. First in late pharyngula stage before hatching, CYP1B1 was constitutively transcribed in retina, midbrain-hindbrain boundary and diencephalon regions through a close coordination between aryl hydrocarbon receptor 2 (AHR2)-dependent and AHR2-independent pathways. After hatching, the basal transcription was attenuated and it could not be elicited upon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. In contrast, TCDD exposure induced de novo CYP1B1 transcription in larval branchial arches and heart tissues via an AHR2-dependent pathway. Blocking AHR2 translation completely eliminated the TCDD-mediated CYP1B1 transcription. However, we did not detect any types of CYP1B1 transcription in liver and kidney tissues through the developmental stage. It suggests that the constitutive and TCDD-inducible types of CYP1B1 transcriptions are modulated by distinct pathways with different tissue specificities. Finally, we investigated the role of CYP1B1 in TCDD-mediated embryonic toxicity. Because knockdown of CYP1B1 did not prevent TCDD-induced pericardial edema and cranial defects, it suggests that CYP1B1 is not involved in the developmental toxicity of dioxin.
细胞色素P450 1B1（CYP1B1）是一种含血红素的单加氧酶，可代谢各种多环芳烃和芳基胺，以及视黄酸和甾体激素。在此我们报告从斑马鱼中克隆出CYP1B1的一个直系同源基因，并证明斑马鱼CYP1B1的转录在不同发育阶段受两种机制调控。首先，在孵化前的咽后期，CYP1B1通过芳烃受体2（AHR2）依赖性和AHR2非依赖性途径之间的紧密协调，在视网膜、中脑 - 后脑边界和间脑区域组成性转录。孵化后，基础转录减弱，并且在暴露于2,3,7,8 - 四氯二苯并 - 对 - 二恶英（TCDD）时无法引发。相反，TCDD暴露通过AHR2依赖性途径在幼虫鳃弓和心脏组织中诱导CYP1B1从头转录。阻断AHR2翻译完全消除了TCDD介导的CYP1B1转录。然而，在整个发育阶段，我们未在肝脏和肾脏组织中检测到任何类型的CYP1B1转录。这表明CYP1B1转录的组成性和TCDD诱导性类型受具有不同组织特异性的不同途径调控。最后，我们研究了CYP1B1在TCDD介导的胚胎毒性中的作用。由于敲低CYP1B1并不能预防TCDD诱导的心包水肿和颅骨缺陷，这表明CYP1B1不参与二恶英的发育毒性。
