title: Evidence for regulation of UDP-glucuronosyltransferase (UGT) 1A1 protein expression and activity via DNA methylation in healthy human livers.
abstract: OBJECTIVE
  Interindividual variability in glucuronidation of bilirubin and drugs by UDP-glucuronosyltransferase 1A1 (UGT1A1) is considerable and only partially explained by genetic polymorphisms and enzyme inducers. Here we determined whether a well-known epigenetic modification, cytosine methylation, explains a proportion of this variability in human liver.
  
  
  METHODS
  UGT1A1 phenotypes, including UGT1A1 protein and bilirubin glucuronidation, and UGT1A1*28 genotype were determined using a human liver bank (n = 46). Methylation levels were quantified at 5 CpG sites associated with known transcription factor response elements in the UGT1A1 promoter and distal enhancer, as well as a CpG-rich island 1.5 kb further upstream.
  
  
  RESULTS
  Individual CpG sites showed considerable methylation variability between livers, ranging from 10- to 29-fold variation with average methylation levels from 25 to 41%. Multivariate regression analysis identified *28/*28 genotype, -4 CpG site methylation and alcohol history as significant predictors of UGT1A1 protein content. Exclusion of livers with *28/*28 genotype or alcohol history revealed positive correlations of -4 CpG methylation with bilirubin glucuronidation (R = 0.73, P < 0.00001) and UGT1A1 protein content (R = 0.54, P = 0.008).
  
  
  CONCLUSIONS
  These results suggest that differential methylation of the -4 CpG site located within a known USF response element may explain a proportion of interindividual variability in hepatic glucuronidation by UGT1A1.
authors: Comparative and Molecular Pharmacogenomics Laboratory, Tufts University School of Medicine, Boston, MA, USA. uyasar@hacettepe.edu.tr
authors: Umit
authors: U
authors: Yasar
authors: David J
authors: DJ
authors: Greenblatt
authors: Chantal
authors: C
authors: Guillemette
authors: Michael H
authors: MH
authors: Court
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001663:Bilirubin / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands / Q000235:genetics; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D003596:Cytosine; D014453:Glucuronosyltransferase; D014157:Transcription Factors; D000099148:UGT1A1 Enzyme
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