title: Expression of UGT2B7 is driven by two mutually exclusive promoters and alternative splicing in human tissues: changes from prenatal life to adulthood and in kidney cancer.
abstract: OBJECTIVE
  UDP-glucuronosyltransferase 2B7 (UGT2B7) plays a major detoxification role in commonly prescribed drugs and endogenous lipophilic molecules. Additional exons and multiple alternative splicing events (ASEs) at the UGT2B7 locus were recently discovered.
  
  
  METHODS
  Novel and classical ASEs were quantified in 27 human tissues, as well as in fetal and tumoral tissues. The activity of the alternative UGT2B7 promoters was studied in cell lines.
  
  
  RESULTS
  UGT2B7 expression is driven by an alternate promoter 1a associated with transcripts containing exon 1b, which is located ∼44 kb upstream of the known promoter 1 associated with transcripts containing exon 1 required for enzyme activity. The exon 1 was expressed most abundantly in the liver and gastrointestinal tract, whereas exon 1b was expressed predominantly in other extrahepatic tissues. Experimental evidence indicated endogenous translation that yields alternative UGT2B7s derived from the use of exon 1b are enzymatically inactive. Alternate 5' ASE predominates in fetal tissues (kidney, lung) and kidney tumor samples compared with normal adult kidney. These changes further correlate with reduced glucuronidation in neoplastic kidneys. This differential expression pattern was further confirmed using four liver and kidney cell lines and was consistent with the differential usage of alternate promoters in hepatic (promoter 1) and kidney cells (1a).
  
  
  CONCLUSIONS
  UGT2B7 is characterized by two mutually exclusive exons 1, both flanked by a unique 5' promoter region. Data also indicated a switch toward functional enzyme upon maturation in the kidney and reversal of this process in neoplastic cells, considerably modifying the glucuronidation potential across human tissues and cells.
authors.affiliation: aPharmacogenomics Laboratory, Centre Hospitalier de l'Université Laval de Québec (CHU de Québec) Research Center and Faculty of Pharmacy bCHU de Québec Research Center and Faculty of Medicine, Laval University, Quebec, Canada cSkaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado dSchool of Medicine, Kidney Center, University of North Carolina, Chapel Hill, North Carolina, USA eDepartment of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ménard
authors.forename: Eric
authors.initials: E
authors.lastname: Lévesque
authors.forename: Sylvia
authors.initials: S
authors.lastname: Chen
authors.forename: Olivier
authors.initials: O
authors.lastname: Eap
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Joy
authors.forename: Lena
authors.initials: L
authors.lastname: Ekström
authors.forename: Anders
authors.initials: A
authors.lastname: Rane
authors.forename: Chantal
authors.initials: C
authors.lastname: Guillemette
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D005091:Exons; D005333:Fetus / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D059368:RNA Isoforms / Q000378:metabolism*
chemical_list: D059368:RNA Isoforms; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase