Epigenetic regulation of the tissue-specific expression of human UDP-glucuronosyltransferase (UGT) 1A10

Abstract

Human UDP-glucuronosyltransferase (UGT) 1A10 is not expressed in the liver; however, UGT1A10 is exclusively expressed in the intestine, contributing to presystemic first-pass metabolism. Earlier studies revealed that hepatocyte nuclear factor (HNF) 1α and Sp1, as well as an intestine-specific transcription factor, caudal type homeobox (Cdx) 2, are involved in the constitutive expression of UGT1A10. However, why UGT1A10 is not expressed in the liver, where HNF1α and Sp1 are abundantly expressed, is unknown. In this study, we sought to elucidate the mechanism, focusing on epigenetic regulation. Bisulfite sequence analysis revealed that the CpG-rich region (-264 to +117) around the UGT1A10 promoter was hypermethylated (89%) in hepatocytes, whereas the UGT1A10 promoter was hypomethylated (11%) in the epithelium of the small intestine. A luciferase assay revealed that the methylation of the UGT1A10 promoter by SssI methylase abrogated transactivity even with overexpressed Cdx2 and HNF1α. The UGT1A10 promoter was highly methylated (86%) in liver-derived HuH-7 cells, where UGT1A10 is not expressed. In contrast, the UGT1A10 promoter was hardly methylated (19%) in colon-derived LS180 cells, where UGT1A10 is expressed. Treatment with 5-aza-2'-deoxycitidine (5-Aza-dC), an inhibitor of DNA methylation, resulted in an increase in UGT1A10 expression only in HuH-7 cells. Moreover, overexpression of HNF1α and Cdx2 further increased UGT1A10 expression only in the presence of 5-Aza-dC. Collectively, we found that DNA hypermethylation would interfere with the binding of HNF1α and Cdx2, resulting in the defective expression of UGT1A10 in human liver. Thus, epigenetic regulation is one of the mechanisms that determine the tissue-specific expression of UGT1A10.

Pharmacogenomics of Human Uridine Diphospho-Glucuronosyltransferases and Clinical Implications

“…UGT1A1 is abundant in the liver but undetectable in the kidney, whereas other UGTs, such as UGT1A10, are absent in the liver but abundant in the gastrointestinal tract. DNA methylation of UGT1A1 , hypoacetylation of histone H3, and decreased binding of HNF1α are involved in differential tissue expression between liver and kidney cell lines 56 , 57 . For instance, the UGT1A10 promoter appears hypermethylated in hepatocytes, and this process would interfere with the binding of the transcription factors HNF1α and Cdx2, resulting in the defective expression of UGT1A10 in the human liver.…”

“…DNA methylation of UGT1A1, hypoacetylation of histone H3, and decreased binding of HNF1α are involved in differential tissue expression between liver and kidney cell lines. 56,57 For instance, the UGT1A10 promoter appears hypermethylated in hepatocytes, and this process would interfere with the binding of the transcription factors HNF1α and Cdx2, resulting in the defective expression of UGT1A10 in the human liver. In turn, the UGT1A10 promoter is hypomethylated in the epithelium of the small intestine, which is consistent with the reported high expression in this tissue.…”

Evaluation of Expression and Glycosylation Status of UGT1A10 in Supersomes and Intestinal Epithelial Cells with a Novel Specific UGT1A10 Monoclonal Antibody

“…It catalyzes the glucuronidation of drugs such as raloxifene and SN-38 (Kemp et al, 2002;Oguri et al, 2004), and xenobiotics such as flavonoids and hydroxyl benzo[a]pyrenes (Zheng et al, 2002;Lewinsky et al, 2005). The expression of UGT1A10 is regulated both epigenetically and transcriptionally in response to oxidative stress or arylhydrocarbon receptor (AhR) agonists (Kalthoff et al, 2010;Oda et al, 2014). UGT1A10 is considered to play a role in the first-pass glucuronidation of some drugs, limiting the oral bioavailability.…”

Brain-derived neurotrophic factor involved epigenetic repression of UGT2B7 in colorectal carcinoma: A mechanism to alter morphine glucuronidation in tumor

“…Some of those regulations can selectively transform the catalyzing activities to their substrates [8–10]. For example, DNA hyper methylations mediated UGT1A1 regression would contribute to irinotecan active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38) inactivation and cytotoxicity increase in human CRC cells.…”