Variation in the expression of cytochrome P450-related miRNAs and transcriptional factors in human livers: Correlation with cytochrome P450 gene phenotypes

Zhang, Haifeng; Zhu, Lili; Yang, Xin; Gao, Na; Fang, Yan; Wen, Qiang; Qiao, Huan

doi:10.1016/j.taap.2020.115389

Cited by 8 publications

(3 citation statements)

References 44 publications

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“…Our study has several limitations. First, a series of miRNAs have been reported to affect CYP3A expression [ 42 , 43 , 44 , 45 , 46 ]. GTEx v8 provides only microRNA precursors but not mature miRNAs that require distinct assay methods and therefore could not be included in the network analysis.…”

Section: Discussionmentioning

confidence: 99%

Transcription Factors and ncRNAs Associated with CYP3A Expression in Human Liver and Small Intestine Assessed with Weighted Gene Co-Expression Network Analysis

et al. 2022

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CYP3A4, CYP3A5, and CYP3A7, which are located in a multigene locus (CYP3A), play crucial roles in drug metabolism. To understand the highly variable hepatic expression of CYP3As, regulatory network analyses have focused on transcription factors (TFs). Since long non-coding RNAs (lncRNAs) likely contribute to such networks, we assessed the regulatory effects of both TFs and lncRNAs on CYP3A expression in the human liver and small intestine, main organs of CYP3A expression. Using weighted gene co-expression network analysis (WGCNA) of GTEx v8 RNA expression data and multiple stepwise regression analysis, we constructed TF-lncRNA-CYP3A co-expression networks. Multiple lncRNAs and TFs displayed robust associations with CYP3A expression that differed between liver and small intestines (LINC02499, HNF4A-AS1, AC027682.6, LOC102724153, and RP11-503C24.6), indicating that lncRNAs contribute to variance in CYP3A expression in both organs. Of these, HNF4A-AS1 had been experimentally demonstrated to affect CYP3A expression. Incorporating ncRNAs into CYP3A expression regulatory network revealed additional candidate TFs associated with CYP3A expression. These results serve as a guide for experimental studies on lncRNA-TF regulation of CYP3A expression in the liver and small intestines.

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Section: Discussionmentioning

confidence: 99%

Transcription Factors and ncRNAs Associated with CYP3A Expression in Human Liver and Small Intestine Assessed with Weighted Gene Co-Expression Network Analysis

et al. 2022

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“…The expression level of drug metabolism enzymes and their regulatory proteins vary greatly between individuals and populations. (Zanger and Schwab, 2013, Zhang et al, 2021) Differences in the activity and expression of these important genes have already been associated to several severe adverse drug events (ADE) such as opioid toxicity and adverse cardiovascular outcomes in individuals taking the antiplatelet drugs, just to name a few. (de Leon et al, 2003, Biswas et al, 2022) Importantly, most studies of these genes have focused on coding variants and have been conducted in mainly European and East Asian populations.…”

Section: Introductionmentioning

confidence: 99%

Leverage drug perturbation to reveal genetic regulators of hepatic gene expression in African Americans

Zhong

Avitia

et al. 2022

Preprint

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BackgroundExpression quantitative loci (eQTL) studies have paved the way in identifying genetic variation impacting gene expression levels. African Americans (AAs) are disproportionately underrepresented in eQTL studies, resulting in a lack of power to identify population-specific regulatory variations especially related to drug response. Specific drugs are known to affect the biosynthesis of drug metabolism enzymes as well as other genes. We used drug perturbation in cultured primary hepatocytes derived from AAs to determine the effect of drug treatment on eQTL mapping and to identify the drug response eQTLs (reQTLs) that show altered effect size following drug treatment.MethodsWhole-genome genotyping (Illumina MEGA array) and RNA-sequencing were performed on 60 primary hepatocyte cultures after treatment with 6 drugs (Rifampin, Phenytoin, Carbamazepine, Dexamethasone, Phenobarbital, and Omeprazole) and at baseline (no treatment). eQTLs were mapped by treatment and jointly using Meta Tissue.ResultsWe found varying transcriptional changes across different drug treatments and identified Nrf2 as a potential general transcriptional regulator. We jointly mapped eQTL with gene expression data for across all drug treatments and baseline which increased our power to detect eQTLs by 2.7-fold. We also identified 2,988 reQTLs (eQTLs with altered effect size after drug treatment), which were more likely to overlap transcription factor binding sites and uncovered a novel reQTL, rs61017966 that increases CYP3A5 gene expression, a major drug metabolizing enzyme responsible for both drug response and adverse events across several drug classes.ConclusionsOur results provide novel insights into the genetic regulation of gene expression in hepatocytes through drug perturbation and provide insight into SNPs that effect the liver’s ability to respond to transcription upregulation.

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“…Age, sex, and genetic variation in cytochrome P450 (CYP) enzymes [29][30][31][32][33] are important factors leading to variability in drug metabolism and disposition. As a result, these factors may also contribute to variation in systemic drug exposure, response including resultant adverse events [22][23][24] and toxicity to a variety of drugs including anticholinergic medications.…”

Section: Introductionmentioning

confidence: 99%

The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs

Trenaman

Bowles

Andrew

et al. 2021

Pharmacology Res & Perspec

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Variation in the expression of cytochrome P450-related miRNAs and transcriptional factors in human livers: Correlation with cytochrome P450 gene phenotypes

Cited by 8 publications

References 44 publications

Transcription Factors and ncRNAs Associated with CYP3A Expression in Human Liver and Small Intestine Assessed with Weighted Gene Co-Expression Network Analysis

Transcription Factors and ncRNAs Associated with CYP3A Expression in Human Liver and Small Intestine Assessed with Weighted Gene Co-Expression Network Analysis

Leverage drug perturbation to reveal genetic regulators of hepatic gene expression in African Americans

The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs

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