Aryl hydrocarbon receptor nuclear translocator in human liver is regulated by miR-24

Oda, Yoshiko; Nakajima, Miki; Mohri, Takuya; Takamiya, Masataka; Aoki, Yasuhiro; Fukami, Tatsuki; Yokoi, Tsuyoshi

doi:10.1016/j.taap.2012.02.012

Cited by 38 publications

(23 citation statements)

References 32 publications

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“…et al, 2012), and miR-27b is known to regulate CYP1B1 (Tsuchiya et al, 2006). MicroR-24 indirectly regulates CYP1A1 through its effects on the Aryl hydrocarbon receptor nuclear translocator (ARNT) (Oda et al, 2012) and HNF4A (Takagi et al, 2010). However, none of these were regulated by rifampin in our studies.…”

Section: Discussioncontrasting

confidence: 59%

Regulation of MicroRNA Expression by Rifampin in Human Hepatocytes

et al. 2013

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Rifampin causes drug interactions by altering hepatic drug metabolism. Because microRNAs (miRNAs) have been shown to regulate genes involved in drug metabolism, we determined the effect of rifampin on the expression of hepatic miRNAs. Primary human hepatocytes from seven subjects were treated with rifampin, and the expression of miRNA and cytochrome P450 (P450) mRNAs was measured by TaqMan assays and RNA-seq, respectively. Rifampin induced the expression of 10 clinically important and 13 additional P450 genes and repressed the expression of 9 other P450 genes (P < 0.05). Rifampin induced the expression of 33 miRNAs and repressed the expression of 35 miRNAs (P < 0.05). Several of these changes were highly negatively correlated with the rifampin-induced changes in the expression of their predicted target P450 mRNAs, supporting the possibility of miRNA-induced regulation of P450 mRNA expression. In addition, several other miRNA changes were positively correlated with the changes in P450 mRNA expression, suggesting similar regulatory mechanisms. Despite the interindividual variability in the rifampin effects on miRNA expression, principal components analysis clearly separated the rifampin-treated samples from the controls. In conclusion, rifampin treatment alters miRNA expression patterns in human hepatocytes, and some of the changes were correlated with the rifampin-induced changes in expression of the P450 mRNAs they are predicted to target.

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Section: Discussioncontrasting

confidence: 59%

Regulation of MicroRNA Expression by Rifampin in Human Hepatocytes

et al. 2013

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“…The cDNA was synthesized from total RNA prepared from cells or human liver samples. The primers for human CYP2A6 (Nakajima et al, 2006b), human b-actin (Oda et al, 2012), and GAPDH (Tsuchiya et al, 2004) were described previously. A 1-mL portion of the reverse-transcribed mixture was added to a PCR mixture containing 10 pmol each primer, 12.5 mL SYBR Premix Ex Taq solution, and 75 nM ROX in a final volume of 25 mL.…”

Section: Methodsmentioning

confidence: 99%

CYP2A7 Pseudogene Transcript Affects CYP2A6 Expression in Human Liver by Acting as a Decoy for miR-126*

et al. 2015

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Human cytochrome P450 (CYP)2A6 is responsible for the metabolic activation of tobacco-related nitrosamines, as well as the metabolism of nicotine and some pharmaceutical drugs. There are large interindividual differences in CYP2A6 activity and expression, largely attributed to genetic polymorphisms. However, the variability was observed within homozygotes of the wild-type CYP2A6 gene. In this study, we investigated the possibility that CYP2A6 might be regulated by microRNA. A luciferase assay revealed that a microRNA recognition element (MRE) of miR-126* found in the 39-untranslated region (UTR) of CYP2A6 mRNA is functional. We established two HEK293 cell lines stably expressing CYP2A6, with one including and the other excluding the full-length 39-UTR (HEK/ 2A6+UTR and HEK/2A6 cells, respectively). Overexpression of miR-126* markedly decreased CYP2A6 protein levels, enzyme activity, and mRNA level in HEK/2A6+UTR cells, whereas it marginally decreased those in HEK/2A6 cells, indicating that the 39-UTR including the MRE is functional for the downregulation of CYP2A6 by miR-126*. The inhibition of miR-126* increased CYP2A6 protein levels in primary human hepatocytes, suggesting that miR-126* downregulates endogenous CYP2A6 expression. In 20 human liver samples, the expression ratios of CYP2A6 and a pseudogene transcript CYP2A7 mRNA were highly variable (CYP2A7/CYP2A6: 0.1 to 12). Interestingly, we found that CYP2A7 was another target of miR-126* and restored the miR-126*-dependent downregulation of CYP2A6 by acting as a decoy for miR-126*. In conclusion, this study demonstrates that human CYP2A6 is post-transcriptionally regulated by miR-126* and that CYP2A7 affects CYP2A6 expression by competing for miR-126* binding.

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“…Another study showed that AHR was modulated by miR-124 in neuroblastoma SK-N-SH cells . In addition, miR-24 was shown to regulate the AHR dimer partner, aryl hydrocarbon receptor nuclear translocator, and thus interfere with expression and induction of CYP1A1 in Huh-7 and HepG2 cells (Oda et al, 2012).…”

Section: Micrornas In Posttranscriptional Gene Regulationmentioning

confidence: 99%

MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy

Tian

et al. 2015

Drug Metabolism and Disposition

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Knowledge of drug absorption, distribution, metabolism, and excretion (ADME) or pharmacokinetics properties is essential for drug development and safe use of medicine. Varied or altered ADME may lead to a loss of efficacy or adverse drug effects. Understanding the causes of variations in drug disposition and response has proven critical for the practice of personalized or precision medicine. The rise of noncoding microRNA (miRNA) pharmacoepigenetics and pharmacoepigenomics has come with accumulating evidence supporting the role of miRNAs in the modulation of ADME gene expression and then drug disposition and response. In this article, we review the advances in miRNA pharmacoepigenetics including the mechanistic actions of miRNAs in the modulation of Phase I and II drug-metabolizing enzymes, efflux and uptake transporters, and xenobiotic receptors or transcription factors after briefly introducing the characteristics of miRNA-mediated posttranscriptional gene regulation. Consequently, miRNAs may have significant influence on drug disposition and response. Therefore, research on miRNA pharmacoepigenetics shall not only improve mechanistic understanding of variations in pharmacotherapy but also provide novel insights into developing more effective therapeutic strategies.

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Aryl hydrocarbon receptor nuclear translocator in human liver is regulated by miR-24

Cited by 38 publications

References 32 publications

Regulation of MicroRNA Expression by Rifampin in Human Hepatocytes

Regulation of MicroRNA Expression by Rifampin in Human Hepatocytes

CYP2A7 Pseudogene Transcript Affects CYP2A6 Expression in Human Liver by Acting as a Decoy for miR-126*

MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy

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