Relation of Transcriptional Factors to the Expression and Activity of Cytochrome P450 and UDP-Glucuronosyltransferases 1A in Human Liver: Co-Expression Network Analysis.
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 GreysWGCNAModule 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.
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Southern Medical University, Guangzhou, China.|Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, China.
Shilong
S
Zhong
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Southern Medical University, Guangzhou, China.|Guangdong Provincial Key Laboratory of New Drug Screening, Department of Biopharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Weichao
W
Han
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Southern Medical University, Guangzhou, China.|Guangdong Provincial Key Laboratory of New Drug Screening, Department of Biopharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Chuqi
C
Hou
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Southern Medical University, Guangzhou, China.|Guangdong Provincial Key Laboratory of New Drug Screening, Department of Biopharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Junjin
J
Liu
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Southern Medical University, Guangzhou, China.|Guangdong Provincial Key Laboratory of New Drug Screening, Department of Biopharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Lili
L
Wu
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Southern Medical University, Guangzhou, China.|Guangdong Provincial Key Laboratory of New Drug Screening, Department of Biopharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Menghua
M
Liu
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Southern Medical University, Guangzhou, China.|Guangdong Provincial Key Laboratory of New Drug Screening, Department of Biopharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Zhi
Z
Liang
Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Haoming
H
Lin
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Southern Medical University, Guangzhou, China.
Lili
L
Zhou
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Southern Medical University, Guangzhou, China. liusw@smu.edu.cn.|Guangdong Provincial Key Laboratory of New Drug Screening, Department of Biopharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. liusw@smu.edu.cn.
Shuwen
S
Liu
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Southern Medical University, Guangzhou, China. tl405@smu.edu.cn.|Guangdong Provincial Key Laboratory of New Drug Screening, Department of Biopharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. tl405@smu.edu.cn.
Lan
L
Tang
D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013379:Substrate Specificity; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D000099148:UGT1A1 Enzyme
D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D004364:Pharmaceutical Preparations; D014157:Transcription Factors; D000099148:UGT1A1 Enzyme; C000716327:NR1I3 protein, human
CYP450; TFs; UGT1A1; activity; sWGCNA
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