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Nuclear receptor interactions in methotrexate induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1)
Author(s) -
Chen Xinrong,
Maiti Smarajit,
Zhang Jimei,
Chen Guangping
Publication year - 2006
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.20149
Subject(s) - pregnane x receptor , nuclear receptor , receptor , reporter gene , chemistry , calcitriol receptor , signal transduction , inducer , dehydroepiandrosterone , methotrexate , sulfotransferase , transfection , endogeny , gene expression , biochemistry , biology , gene , hormone , enzyme , transcription factor , immunology , androgen
Abstract Cytosolic sulfotransferases (SULTs) are a major family of phase II drug‐metabolizing enzymes. SULT‐catalyzed sulfonation regulates hormone activities metabolizes drugs detoxifies xenobiotic toxicants bioactivates carcinogens. Human dehydroepiandrosterone sulfotransferase (hSULT2A1 DHEA‐ST) plays a very important role in sulfating endogenous hydroxysteroids and exogenousxenobiotics. Our recent studies have shown that methotrexate can induce hSULT2A1 expression. To investigate the molecular mechanism involved in hSULT2A1 induction we generated the promoter sequence of hSULT2A1 by PCR and constructed a reporter gene vector. Both reporter gene assay and endogenous induction results suggested that human constitutive active receptor (hCAR) mediates the methotrexate induction of hSULT2A1 in both Caco‐2 and Hep G2 cells. Human vitamin D receptor (hVDR) also upregulated hSULT2A1 gene expression while human pregnane X receptor (hPXR) downregulated it. Human pregnane X receptor suppressed hCAR‐mediated methotrexate induction of hSULT2A1 in both Caco‐2 and Hep G2 cells. hVDR competed with hCAR for the hSULT2A1 promoter in Caco‐2 cells. hCAR inhibited hVDR‐mediated vitamin D3 induction of hSULT2A1 but not methotrexate induction of hSULT2A1. These results strongly support the hypothesis that cross‐talk occurs among nuclear receptors in the signal transduction pathway of hSULT2A1 and that interactions among nuclear receptors also depend on ligands (inducers) in the system. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:309–317, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20149