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Title: Regulation of zebrafish CYP3A65 transcription by AHR2

Abstract

CYP3A proteins are the most abundant CYPs in the liver and intestines, and they play a pivotal role in drug metabolism. In mammals, CYP3A genes are induced by various xenobiotics through processes mediated by PXR. We previously identified zebrafish CYP3A65 as a CYP3A ortholog that is constitutively expressed in gastrointestinal tissues, and is upregulated by treatment with dexamethasone, rifampicin or tetrachlorodibenzo-p-dioxin (TCDD). However, the underlying mechanism of TCDD-mediated CYP3A65 transcription is unclear. Here we generated two transgenic zebrafish, Tg(CYP3A65S:EGFP) and Tg(CYP3A65L:EGFP), which contain 2.1 and 5.4 kb 5′ flanking sequences, respectively, of the CYP3A65 gene upstream of EGFP. Both transgenic lines express EGFP in larval gastrointestinal tissues in a pattern similar to that of the endogenous CYP3A65 gene. Moreover, EGFP expression can be significantly induced by TCDD exposure during the larval stage. In addition, EGFP expression can be stimulated by kynurenine, a putative AHR ligand produced during tryptophan metabolism. AHRE elements in the upstream regulatory region of the CYP3A65 gene are indispensible for basal and TCDD-induced transcription. Furthermore, the AHR2 DNA and ligand-binding domains are required to mediate effective CYP3A65 transcription. AHRE sequences are present in the promoters of many teleost CYP3 genes, but not of mammalian CYP3 genes, suggestingmore » that AHR/AHR2-mediated transcription is likely a common regulatory mechanism for teleost CYP3 genes. It may also reflect the different environments that terrestrial and aquatic organisms encounter. - Highlights: • Tg(CYP3A65:EGFP) and CYP3A65 exhibits identical expression pattern. • CYP3A65 can be significantly induced by TCDD or kynurenine. • The AHRE elements are required to mediate CYP3A65 transcription. • The AHR2 DNA and ligand-binding domains are required for CYP3A65 transcription. • AHRE elements are present in many teleost CYP3 genes, but not in mammalian CYP3 genes.« less

Authors:
; ; ;  [1];  [1];  [2];  [1];  [2]
  1. Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan (China)
  2. (China)
Publication Date:
OSTI Identifier:
22285344
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 270; Journal Issue: 2; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIBIOTICS; DEXAMETHASONE; DIOXIN; DNA; GENES; INTESTINES; KYNURENINE; LIVER; METABOLISM; TRANSCRIPTION; TRYPTOPHAN

Citation Formats

Chang, Chin-Teng, Chung, Hsin-Yu, Su, Hsiao-Ting, Tseng, Hua-Pin, Tzou, Wen-Shyong, Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan, Hu, Chin-Hwa, E-mail: chhu@mail.ntou.edu.tw, and Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan. Regulation of zebrafish CYP3A65 transcription by AHR2. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2013.04.010.
Chang, Chin-Teng, Chung, Hsin-Yu, Su, Hsiao-Ting, Tseng, Hua-Pin, Tzou, Wen-Shyong, Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan, Hu, Chin-Hwa, E-mail: chhu@mail.ntou.edu.tw, & Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan. Regulation of zebrafish CYP3A65 transcription by AHR2. United States. doi:10.1016/J.TAAP.2013.04.010.
Chang, Chin-Teng, Chung, Hsin-Yu, Su, Hsiao-Ting, Tseng, Hua-Pin, Tzou, Wen-Shyong, Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan, Hu, Chin-Hwa, E-mail: chhu@mail.ntou.edu.tw, and Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan. Mon . "Regulation of zebrafish CYP3A65 transcription by AHR2". United States. doi:10.1016/J.TAAP.2013.04.010.
@article{osti_22285344,
title = {Regulation of zebrafish CYP3A65 transcription by AHR2},
author = {Chang, Chin-Teng and Chung, Hsin-Yu and Su, Hsiao-Ting and Tseng, Hua-Pin and Tzou, Wen-Shyong and Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan and Hu, Chin-Hwa, E-mail: chhu@mail.ntou.edu.tw and Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan},
abstractNote = {CYP3A proteins are the most abundant CYPs in the liver and intestines, and they play a pivotal role in drug metabolism. In mammals, CYP3A genes are induced by various xenobiotics through processes mediated by PXR. We previously identified zebrafish CYP3A65 as a CYP3A ortholog that is constitutively expressed in gastrointestinal tissues, and is upregulated by treatment with dexamethasone, rifampicin or tetrachlorodibenzo-p-dioxin (TCDD). However, the underlying mechanism of TCDD-mediated CYP3A65 transcription is unclear. Here we generated two transgenic zebrafish, Tg(CYP3A65S:EGFP) and Tg(CYP3A65L:EGFP), which contain 2.1 and 5.4 kb 5′ flanking sequences, respectively, of the CYP3A65 gene upstream of EGFP. Both transgenic lines express EGFP in larval gastrointestinal tissues in a pattern similar to that of the endogenous CYP3A65 gene. Moreover, EGFP expression can be significantly induced by TCDD exposure during the larval stage. In addition, EGFP expression can be stimulated by kynurenine, a putative AHR ligand produced during tryptophan metabolism. AHRE elements in the upstream regulatory region of the CYP3A65 gene are indispensible for basal and TCDD-induced transcription. Furthermore, the AHR2 DNA and ligand-binding domains are required to mediate effective CYP3A65 transcription. AHRE sequences are present in the promoters of many teleost CYP3 genes, but not of mammalian CYP3 genes, suggesting that AHR/AHR2-mediated transcription is likely a common regulatory mechanism for teleost CYP3 genes. It may also reflect the different environments that terrestrial and aquatic organisms encounter. - Highlights: • Tg(CYP3A65:EGFP) and CYP3A65 exhibits identical expression pattern. • CYP3A65 can be significantly induced by TCDD or kynurenine. • The AHRE elements are required to mediate CYP3A65 transcription. • The AHR2 DNA and ligand-binding domains are required for CYP3A65 transcription. • AHRE elements are present in many teleost CYP3 genes, but not in mammalian CYP3 genes.},
doi = {10.1016/J.TAAP.2013.04.010},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 270,
place = {United States},
year = {Mon Jul 15 00:00:00 EDT 2013},
month = {Mon Jul 15 00:00:00 EDT 2013}
}
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