Journal article
Evidence for regulation of UDP‐glucuronosyltransferase (UGT) 1A1 protein expression and activity via DNA methylation in healthy human livers
Journal of pharmacy and pharmacology, Vol.65(6), pp.874-883
06/2013
Handle:
https://hdl.handle.net/2376/103846
PMID: 23647681
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 1.5 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.
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Details
- Title
- Evidence for regulation of UDP‐glucuronosyltransferase (UGT) 1A1 protein expression and activity via DNA methylation in healthy human livers
- Creators
- Umit Yasar - Tufts University School of MedicineDavid J Greenblatt - Tufts University School of MedicineChantal Guillemette - Laval UniversityMichael H Court - Tufts University School of Medicine
- Publication Details
- Journal of pharmacy and pharmacology, Vol.65(6), pp.874-883
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Number of pages
- 10
- Grant note
- NIH (R01‐GM061834; #N01‐DK‐7‐0004/HHSN267200700004C) Canadian Institutes of Health Research (MOP‐42392) Canada Research Chair Program
- Identifiers
- 99900546533801842
- Language
- English
- Resource Type
- Journal article