Regulation of Hepatic UGT2B15 by Methylation in Adults of Asian Descent.

Steffen Oeser,Abby Collier,Jon-Paul Bingham

doi:10.3390/pharmaceutics10010006

Abstract

The hepatic uridine 5′-diphosphate-glucuronosyl transferases (UGTs) are critical for detoxifying endo- and xenobiotics. Since UGTs are also dynamically responsive to endogenous and exogenous stimuli, we examined whether epigenetic DNA methylation can regulate hepatic UGT expression and differential effects of ethnicity, obesity, and sex. The methylation status of UGT isoforms was determined with Illumina Methylation 450 BeadChip arrays, with genotyping confirmed by sequencing and gene expression confirmed with quantitative reverse transcriptase polymerase chain reaction (q-RT-PCR). The UGT1A3 mRNA was 2-fold higher in females than males (p < 0.05), while UGT1A1 and UGT2B7 mRNA were significantly higher in Pacific Islanders than Caucasians (both p < 0.05). Differential mRNA or methylation did not occur with obesity. The methylation of the UGT2B15 locus cg09189601 in Caucasians was significantly lower than the highly methylated locus in Asians (p < 0.001). Three intergenic loci between UGT2B15 and 2B17 (cg07973162, cg10632656, and cg07952421) showed higher rates of methylation in Caucasians than in Asians (p < 0.001). Levels of UGT2B15 and UGT2B17 mRNA were significantly lower in Asians than Caucasians (p = 0.01 and p < 0.001, respectively). Genotyping and sequencing indicated that only UGT2B15 is regulated by methylation, and low UGT2B17 mRNA is due to a deletion genotype common to Asians. Epigenetic regulation of UGT2B15 may predispose Asians to altered drug and hormone metabolism and begin to explain the increased risks for adverse drug reactions and some cancers in this population.

Highlights

The uridine 50 -diphosphate-glucuronosyl transferases (UGTs, E.C. 2.4.1.17) primarily eliminate xeno- and endobiotics in humans through conjugating them with a polar sugar [1]
Other than the findings presented for individuals of Asian descent, methylation did not regulate UGT1A or UGT2B isoforms with age, ethnicity, obesity, or sex in this cohort
We believe that future work in this area will need to encompass protein-level studies with Western blot of UGT2B15 and/or activity studies to confirm if these results found at the mRNA levels follow through to the levels of enzyme proteins and their function

Summary

Introduction

The uridine 50 -diphosphate-glucuronosyl transferases (UGTs, E.C. 2.4.1.17) primarily eliminate xeno- and endobiotics in humans through conjugating them with a polar sugar [1]. In conjunction with other enzymes, the UGTs are involved in the clearance of more than 90% of clinically relevant drugs from the body [2]. Based on nucleotide sequence analysis, 22 human UGT proteins have been identified in 4 families, with the UGT1A and UGT2B subfamilies being most critical for hepatic metabolism [3,4,5]. The UGT enzymes are genetically polymorphic, with over 200 variant alleles described for the UGT1 and UGT2 subfamilies that can influence enzymatic function, cellular trafficking, or gene expression, modifying individual drug and endobiotic exposure [6]. Some of these single nucleotide polymorphisms (SNPs) are functional, changes in total glucuronidation tend to occur when many polymorphisms are inherited together as a haplotype [6]

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