An Alternative Promoter Contributes to Tissue- and Inducer-Specific Expression of the Rat UDP-Glucuronosyltransferase 1A6 Gene

• Published in: Toxicology and applied pharmacology Vol. 174; no. 1; pp. 60 - 68
• Main Authors: Auyeung, Diana J., Kessler, Fay K., Ritter, Joseph K.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.07.2001; Elsevier
• Subjects: 1A6 gene; 5' Untranslated Regions; alternative promoter; amines; Animals; Base Sequence; Benzo(a)pyrene - pharmacology; benzo[a]pyrene; beta-Naphthoflavone - pharmacology; Biological and medical sciences; Chemical and industrial products toxicology. Toxic occupational diseases; Digestive System - enzymology; DNA, Complementary - chemistry; Exons; Gene Expression; gene regulation; glucuronidation; Glucuronosyltransferase - genetics; hepatic nuclear factor; Humans; Kidney - enzymology; Liver - enzymology; Male; Medical sciences; Methylcholanthrene - pharmacology; Molecular Sequence Data; Promoter Regions, Genetic; Pyrazines - pharmacology; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Sequence Alignment; Toxicology; UDP-glucuronosyltransferase; Various organic compounds; benzo[a]pyrene; alternative promoter; UDP-glucuronosyltransferase; gene regulation; hepatic nuclear factor; 5' terminal-Sequence; Rat; Nucleotide sequence; Transcription; Enzyme; Isozyme; Transcription promoter; Toxicity; Transferases; Chemical compound; Glycosyltransferases; Rodentia; Tissue specificity; Gene expression; Vertebrata; Mammalia; Animal; Hexosyltransferases
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.2001.9191

UDP-glucuronosyltransferase 1A6 (UGT1A6), a key enzyme catalyzing the glucuronidation of small planar phenols and amines, is expressed in a tissue- and inducer-dependent manner. Expression is high in kidney, gastrointestinal tract, and induced liver, with low expression in spleen, lung, and ovary. Exposure to certain chemicals, such as 3-methylcholanthrene, benzo[a]pyrene, β-naphthoflavone, and oltipraz elevates UGT1A6 mRNA in liver and to a lesser extent gastrointestinal tract and kidney, but not in other tissues. The mechanisms underlying this complex pattern of expression have been elusive. We have identified a new type of UGT1A6 mRNA (class 2) that differs in its 5′ untranslated sequence. The class 2 transcript is the more abundant type expressed in liver, gastrointestinal tract, and kidney. Transcription of the class 2 mRNA is initiated 107 bases 5′ of the UGT1A6 coding exon. The promoter region flanking the transcription start site contains an HNF1-like binding site identical to that in the human UGT1A6 gene. Both class 1 and class 2 mRNAs were elevated in liver by 3-methylcholanthrene, benzo[a]pyrene, β-naphthoflavone, and oltipraz, with preferential elevation of class 1 occurring after 3-methylcholanthrene and benzo[a]pyrene treatment. These data suggest that transcription from a second promoter contributes to tissue- and inducer-specific expression of rat UGT1A6.