AH receptor-controlled transcriptional regulation and function of rat and human UDP-glucuronosyltransferase isoforms.
Transcriptional regulation and function of rat and human PAH-inducible UDP-glucuronosyltransferase (UGT) isoforms have been studied. 1. At least two PAH-inducible UGT isoforms are expressed in a variety of tissues, the rat isoforms UGT1A6 and UGT1A7, and the human isoforms UGT1A6 and UGT1A9. 2. For the rat and human UGT1A6 isoforms two modes of tissue- and cell-specific regulation were found, PAH-inducible and constitutive expression. 3. Transient transfection studies, using human UGT1A6/CAT fusion constructs and colon carcinoma Caco-2 cells, revealed that PAH induction of human UGT1A6 is mediated by the Ah receptor. 4. Cell-expressed UGT isoforms were used to study their function in PAH metabolism. Rat UGT1A7 and human UGT1A9 appear to be more efficient than the corresponding UGT1A6 isoforms in catalyzing glucuronide formation of PAH phenols and diphenols. Several isoforms may act together in the formation of benzo(a)pyrene-3.6-diol diglucuronide, the major glucuronide found in rat bile. The results suggest complex modes of transcriptional regulation of PAH-inducible UGTs. They also suggest a major role of these UGT isoforms in detoxication of PAHs.
Institute of Toxicology, University of Tübingen, Germany.
K W
KW
Bock
H
H
Gschaidmeier
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H
Heel
T
T
Lehmköster
P A
PA
Münzel
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F
Raschko
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B
Bock-Hennig
D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D015394:Molecular Structure; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
D005965:Glucuronates; D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D011084:Polycyclic Aromatic Hydrocarbons; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014453:Glucuronosyltransferase