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Molecular Pharmacology

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Research ArticleArticle

Characterization of the Zebrafish Ugt Repertoire Reveals a New Class of Drug-Metabolizing UDP Glucuronosyltransferases

Yuanming Wang, Haiyan Huang and Qiang Wu
Molecular Pharmacology July 2014, 86 (1) 62-75; DOI: https://doi.org/10.1124/mol.113.091462
Yuanming Wang
Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, and State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, and Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Center, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
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Haiyan Huang
Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, and State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, and Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Center, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
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Qiang Wu
Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, and State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, and Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Center, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
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Abstract

The zebrafish genome contains a gene superfamily of 40 Ugt genes that can be divided into Ugt1, Ugt2, and Ugt5 families. Because the encoded zebrafish UDP glucuronosyltransferase (UGT) proteins do not display orthologous relationships to any of the mammalian and avian UGT enzymes based on molecular phylogeny, it is difficult to predict their substrate specificity. Here, we mapped their tissue-specific expression patterns. We showed that the zebrafish UGT enzymes can be glycosylated. We determined their substrate specificity and catalytic activity toward diverse aglycone substrates. Specifically, we measured mRNA levels of each of the 40 zebrafish Ugt genes in 11 adult tissues and found that they are expressed in a tissue-specific manner. Moreover, functional analyses with the donor of UDP glucuronic acid (UDPGA) for each of the 40 zebrafish UGT proteins revealed their substrate specificity toward 10 important aglycones. In particular, UGT1A1, UGT1A7, and UGT1B1 displayed good glucuronidation activities toward most phenolic aglycones (4-methylumbelliferone, 4-nitrophenol, 1-naphthol, bisphenol A, and mycophenolic acid) and the two carboxylic acids (bilirubin and diclofenac). Importantly, some members of the UGT5, a novel UGT family identified recently, are capable of glucuronidating multiple aglycones with the donor cofactor of UDPGA. In particular, UGT5A5, UGT5B2, and UGT5E1 glucuronidate phenols and steroids with high specificity toward steroid hormones of estradiol and testosterone and estrogenic alkylphenols 4-tert-octylphenol. These results shed new insights into the mechanisms by which fish species defend themselves against vast numbers of xenobiotics via glucuronidation conjugations and may facilitate the establishment of zebrafish as a model vertebrate in toxicological, developmental, and pathologic studies.

Footnotes

    • Received December 24, 2013.
    • Accepted April 11, 2014.
  • Y.W. and H.H. contributed equally to this work.

  • This work was supported by the National Natural Science Foundation for the Youth of China [Grant 81302861]; the Program of Shanghai Subject Chief Scientist to Q.W.; the Ministry of Science and Technology of China [Grant 2009CB918700]; the National Natural Science Foundation of China [Grants 31171015 and 30970669]; and the Science and Technology Commission of Shanghai Municipality [Grant 09PJ1405300].

  • dx.doi.org/10.1124/mol.113.091462.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (1)
Molecular Pharmacology
Vol. 86, Issue 1
1 Jul 2014
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Research ArticleArticle

Glucuronidation Activity of the Zebrafish UGT Superfamily

Yuanming Wang, Haiyan Huang and Qiang Wu
Molecular Pharmacology July 1, 2014, 86 (1) 62-75; DOI: https://doi.org/10.1124/mol.113.091462

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Research ArticleArticle

Glucuronidation Activity of the Zebrafish UGT Superfamily

Yuanming Wang, Haiyan Huang and Qiang Wu
Molecular Pharmacology July 1, 2014, 86 (1) 62-75; DOI: https://doi.org/10.1124/mol.113.091462
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