Regulation of Mammalian UDP-Glucuronosyltransferases

Author(s): Hong Wang, Guoxiu Cao, Guangji Wang*, Haiping Hao*.

Journal Name: Current Drug Metabolism

Volume 19 , Issue 6 , 2018

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Abstract:

Background: UDP-glucuronosyltransferases (UGTs) are a class of important phase II drug metabolizing enzymes (DMEs), playing essential roles in the homeostasis of endobiotics as well as the dispositional behavior of exogenous compounds. The expression and enzyme activity of UGTs are regulated by multiple dimensions of mechanisms and can be influenced by diverse factors. Thus, the intensive research of its regulatory network is pivotal for better understanding about the physiological, pathological, and therapeutic significance of UGTs. Despite the lag to the research in cytochrome P450s, extensive efforts have been made to advance the understanding of the regulatory network of UGTs in recent years.

Method: This review presents a comprehensive summary and intensive discussion about the recent advancement on the regulatory network of UGTs.

Results: UGTs can be regulated at the epigenetic level via DNA methylation and histone modification. Various nuclear receptors can influence the mRNA levels of UGTs in a ligand dependent manner. Some general transcriptional factors such as AP-1, NF-κB, and p53, and some tissue specific transcriptional factors including HFN1α and HNF4α can also regulate UGTs at the transcriptional level. Multiple miRNAs have been found to be involved in the regulation of UGTs at post-transcriptional level. UGT proteins can be directly regulated via various post-translational modifications, protein-protein interactions, and protein-chemicals interactions, leading to the alternation of enzyme activities.

Conclusion: In addition to the well-defined genetic polymorphism that induce individual variation of UGTs, this review reinforces the importance of other mechanisms that are critical for the regulation of UGTs.

Keywords: UGT, regulation, transcriptional factors, DNA methylation, histone modification, miRNAs, post-translational modifications.

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Article Details

VOLUME: 19
ISSUE: 6
Year: 2018
Page: [490 - 501]
Pages: 12
DOI: 10.2174/1389200219666180307122945
Price: $58

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