Evidence for regulation of UDP-glucuronosyltransferase (UGT) 1A1 protein expression and activity via DNA methylation in healthy human livers

J Pharm Pharmacol. 2013 Jun;65(6):874-83. doi: 10.1111/jphp.12053. Epub 2013 Mar 21.


Objectives: 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.

Key findings: 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).

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Bilirubin / metabolism
  • Child
  • Child, Preschool
  • CpG Islands / genetics
  • Cytosine / metabolism
  • DNA Methylation*
  • Epigenesis, Genetic / genetics
  • Female
  • Genotype
  • Glucuronosyltransferase / genetics*
  • Glucuronosyltransferase / metabolism*
  • Humans
  • Liver / enzymology*
  • Liver / metabolism
  • Liver / physiology*
  • Male
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Middle Aged
  • Phenotype
  • Polymorphism, Genetic
  • Promoter Regions, Genetic
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Young Adult


  • Transcription Factors
  • Cytosine
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Bilirubin