title: Gender matters: estrogen receptor alpha (ERα) and histone deacetylase (HDAC) 1 and 2 control the gender-specific transcriptional regulation of human uridine diphosphate glucuronosyltransferases genes (UGT1A).
abstract: OBJECTIVE
  Gender influences incidence, progression, and therapy of hepatogastrointestinal diseases. The aim of this study was to elucidate the molecular mechanism of gender-specific UDP-glucuronosyltransferases (UGT1A) regulation, representing important hepatogastrointestinal detoxification enzymes for xenobiotics, drugs, and endobiotics.
  
  
  METHODS
  UGT1A-gene activation was studied by reporter gene experiments and estrogen receptor alpha (ESR1/ERα) co-transfection using KYSE70- and HepG2 cells (male origin), and SW403 cells (female origin). Cell lines, and humanized transgenic UGT1A (htgUGT1A) mice (female/male) were treated with the ERα inhibitor tamoxifen. UGT1A mRNA expression was analyzed by TaqMan PCR, the recruitment of ERα, histone deacetylases (HDAC), and the aryl hydrocarbon receptor (AhR) by chromatin immunoprecipitation (ChIP), and ERα expression in gastrointestinal mouse tissues by Western blot and immunofluorescence.
  
  
  RESULTS
  In KYSE70 cells (male), UGT1A gene expression was induced 5-10 fold, and inhibited in the presence of ERα by 55-77%. In SW403 (female) cells, absent inducibility was restored after tamoxifen treatment. In the jejunum and colon of tgUGT1A mice, UGT1A induction that was exclusively detected in male mice could be restored in female mice after tamoxifen pre-treatment. ChIP assays demonstrated the recruitment of ERα and HDACs to the xenobiotic response elements of UGT1A promoters during gene repression. Western blot showed higher ERα expression in the female jejunum and colon.
  
  
  CONCLUSIONS
  We show gender-specific transcriptional control of UGT1A genes in jejunum and colon, which is repressed by ERα and the recruitment of HDCAs to the UGT1A promoter sequence in females. A molecular mechanism controlling gender-specific drug metabolism and its therapeutic reversal is demonstrated.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kalthoff
authors.forename: Anja
authors.initials: A
authors.lastname: Winkler
authors.forename: Nicole
authors.initials: N
authors.lastname: Freiberg
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Christian P
authors.initials: CP
authors.lastname: Strassburg
mesh_terms: D000818:Animals; D002460:Cell Line; D003069:Coffee; D003106:Colon / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics*; D056945:Hep G2 Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007583:Jejunum / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D012727:Sex Characteristics; D013629:Tamoxifen / Q000494:pharmacology; D000099148:UGT1A1 Enzyme
chemical_list: D003069:Coffee; D047628:Estrogen Receptor alpha; D014453:Glucuronosyltransferase; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D000099148:UGT1A1 Enzyme; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human
keywords: 2,3,7,8-tetrachlordibenzo-p-dioxin; AhR; CAR; CYP; Drug metabolism; ERα; Gender; HDAC; HNF4(α); Nrf2; PCR; PPARA; PXR; TCDD; UDP-glucuronosyltransferase; UGT; XRE; arylhydrocarbon receptor; constitutive androstane receptor; cytochrome P450 enzyme; estrogen receptor alpha; hepatocyte nuclear factor 4 alpha; histone deacetylase; nuclear factor erythroid related factor 2; peroxisome proliferator-activated receptor alpha; polymerase chain reaction; pregnane X receptor; tBHQ; tert-butylhydroquinone; xenobiotic response element