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


Yasar U., Greenblatt D. J., Guillemette C., Court M. H.

JOURNAL OF PHARMACY AND PHARMACOLOGY, vol.65, no.6, pp.874-883, 2013 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 65 Issue: 6
  • Publication Date: 2013
  • Doi Number: 10.1111/jphp.12053
  • Journal Name: JOURNAL OF PHARMACY AND PHARMACOLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.874-883
  • Hacettepe University Affiliated: Yes

Abstract

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 1.5kb 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.