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, cilt.65, ss.874-883, 2013 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 65 Konu: 6
  • Basım Tarihi: 2013
  • Doi Numarası: 10.1111/jphp.12053
  • Dergi Adı: JOURNAL OF PHARMACY AND PHARMACOLOGY
  • Sayfa Sayıları: ss.874-883

Özet

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.