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Relation of Transcriptional Factors to the Expression and Activity of Cytochrome P450 and UDP-Glucuronosyltransferases 1A in Human Liver: Co-Expression Network Analysis

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Abstract

Cytochrome P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) play important roles in the metabolism of exogenous and endogenous compounds. The gene transcription of CYPs and UGTs can be enhanced or reduced by transcription factors (TFs). This study aims to explore novel TFs involved in the regulatory network of human hepatic UGTs/CYPs. Correlations between the transcription levels of 683 key TFs and CYPs/UGTs in three different human liver expression profiles (n = 640) were calculated first. Supervised weighted correlation network analysis (sWGCNA) was employed to define hub genes among the selected TFs. The relationship among 17 defined TFs, CYPs/UGTs expression, and activity were evaluated in 30 liver samples from Chinese patients. The positive controls (e.g., PPARA, NR1I2, NR1I3) and hub TFs (NFIA, NR3C2, and AR) in the GreysWGCNA Module were significantly and positively associated with CYPs/UGTs expression. And the cancer- or inflammation-related TFs (TEAD4, NFKB2, and NFKB1) were negatively associated with mRNA expression of CYP2C9/CYP2E1/UGT1A9. Furthermore, the effect of NR1I2, NR1I3, AR, TEAD4, and NFKB2 on CYP450/UGT1A gene transcription translated into moderate influences on enzyme activities. To our knowledge, this is the first study to integrate Gene Expression Omnibus (GEO) datasets and supervised weighted correlation network analysis (sWGCNA) for defining TFs potentially related to CYPs/UGTs. We detected several novel TFs involved in the regulatory network of hepatic CYPs and UGTs in humans. Further validation and investigation may reveal their exact mechanism of CYPs/UGTs regulation.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Nos. 81673677, 81503376, and 81673514), the Natural Science Foundation of Guangdong Province (2016A030313592), Applied Science And Technology Research Foundation of Guangdong Province (2016B020237005), and the Foundation for Distinguished Young Teachers in Higher Education of Guangdong (Yq2013037).

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    Authors and Affiliations

    1. State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Southern Medical University, Guangzhou, China

      Shilong Zhong, Weichao Han, Chuqi Hou, Junjin Liu, Lili Wu, Menghua Liu, Zhi Liang, Lili Zhou, Shuwen Liu & Lan Tang

    2. Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, China

      Shilong Zhong

    3. Guangdong Provincial Key Laboratory of New Drug Screening, Department of Biopharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China

      Weichao Han, Chuqi Hou, Junjin Liu, Lili Wu, Menghua Liu, Zhi Liang, Shuwen Liu & Lan Tang

    4. Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

      Haoming Lin

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    Informed consents were obtained from all participants. Approval for tissue collection and in vitro drug metabolism studies were obtained from the ethics committee of Sun Yat-Sen Memorial Hospital (ECSYS no. CS07095).

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    Shilong Zhong, Weichao Han and Chuqi Hou contributed equally to this work.

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    Figure S1

    Mass spectrum of omeprazole, midazolam, chlorzoxazone, tolbutamide and their metabolites. (GIF 102 kb)

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    UPLC profiles of testosterone, genistein, SN38, mycophenolic acid and their metabolites. (GIF 77 kb)

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    Figure S3

    Frequency distribution of CYP2C9, CYP2C19, CYP2E1, CYP3A4, CYP3A5, UGT1A1, UGT1A9 and UGT1As activities in Hungarian liver donors (n = 30). (GIF 121 kb)

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    Zhong, S., Han, W., Hou, C. et al. Relation of Transcriptional Factors to the Expression and Activity of Cytochrome P450 and UDP-Glucuronosyltransferases 1A in Human Liver: Co-Expression Network Analysis. AAPS J 19, 203–214 (2017). https://doi.org/10.1208/s12248-016-9990-2

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