MicroRNAs Regulate CYP3A4 Expression via Direct and Indirect Targeting

Pan, Yu; Gao, Wenqing; Jilek, Joseph L.

doi:10.1124/dmd.109.027680

Cited by 236 publications

(205 citation statements)

References 29 publications

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“…Considerable efforts have been made recently to elucidate the roles of specific miRNA species in regulating DME expression. MiRNAs have been shown to affect the expression of many DMEs, including CYP1B1 [18],CYP2E1 [19], CYP3A4 [20] and SULT1A1 [21]. In the case of CYP2C19, two miRNA binding sites were identified within its 3′-UTR that interacted with miR-103 or miR-107 [22].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

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Tolleson

et al. 2015

Biochemical Pharmacology

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Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of many drugs. Extensive studies have demonstrated that genetic variants and endogenous and environmental factors play important roles in the expression of CYP2C19. However, the role of microRNAs (miRNAs) in controlling CYP2C19 expression has not been investigated completely. In the present study, we performed in silico analysis to rank putative miRNA/CYP2C19 hybrids with regards to the predicted stabilities of their duplexes and then we applied a series of biochemical and molecular assays to elucidate the underlying functional mechanisms for the regulation of CYP2C19 by miRNAs. In silico analysis indicated that hsa-miR-23a-3p and hsa-miR-29a-3p target the coding region of CYP2C19 with hybrid stabilities of −27.5 kcal/mol and −23.3 kcal/mol, respectively. RNA electrophoresis mobility shift assays showed that both hsa-miR-23a-3p and hsa-miR-29a-3p miRNAs were able to bind directly to their cognate targets in the CYP2C19 transcript. Further, a significant inverse correlation was found between chemically-induced up-regulation of hsamiR-29a-3p and CYP2C19 expression in HepaRG cells. In addition, inverse correlations were also observed in human liver tissue samples between the level of CYP2C19 mRNA expression and both hsa-miR-23a-3p and hsa-miR-29a-3p levels. All these results demonstrated the suppressing role of hsa-miR-29a-3p on CYP2C19 expression.

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Section: Introductionmentioning

confidence: 99%

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

Green

Tolleson

et al. 2015

Biochemical Pharmacology

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“…In contrast, the CYP3A4 protein level showed a significantly positive correlation with the CYP3A4 mRNA level indicating that the transcriptional regulation mainly contributes to the expression. Although we didn't examine CYP3A4 further, Pan et al (2009a) subsequently reported that CYP3A4 protein in LS180 and human pancreas cancer-derived PANC1 cells was decreased by the overexpression of miR-27b, accompanied by a decrease of the CYP3A4 mRNA level. A limitation of their study may be that the conclusion was drawn from only an overexpression study.…”

Section: Cyp3a4 and Pregnane X Receptor (Pxr)mentioning

confidence: 98%

“…Pan et al (2009a) have reported, using LS180 and PANC1 cells, that overexpression of miR-27b decreased the expression of VDR. Ji et al (2009) have reported, using rat hepatic stellate cells, that the inhibition of miR-27a and miR-27b increased the expression of retinoid X receptor α (RXRα), a heterodimer partner of various nuclear receptors such as PXR, VDR, CAR, PPAR, farnesoid X receptor, and liver X receptor.…”

Section: Lin Et Al (2009) Have Reported Using Mouse Embryonic Fibrobmentioning

confidence: 99%

MicroRNAs from biology to future pharmacotherapy: Regulation of cytochrome P450s and nuclear receptors

Nakajima

Yokoi

2011

Pharmacology & Therapeutics

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MicroRNAs (miRNAs) are a family of short, non-coding RNA whose final product is a 22-nucleotide functional RNA molecule. They regulate the expression of target genes by binding to complementary regions of transcripts to repress their translation or promote mRNA degradation. Since miRNAs regulate every aspect of cellular function, their dysregulation is associated with a variety of diseases including cancer, diabetes, and cardiovascular diseases.Therefore, miRNAs are now considered new therapeutic targets. However, the roles of miRNAs in the metabolism of xenobiotics and endobiotics have only recently been revealed.This review describes the current knowledge on the regulation of cytochrome P450s and nuclear receptors by miRNAs, the physiological and clinical significance. The miRNA expression is readily altered by chemicals, carcinogens, drugs, hormones, stress, or diseases, and the dysregulation of specific miRNAs might lead to changes in the drug metabolism potency or pharmacokinetics as well as pathophysiological changes. In the field of pharmacogenomics, the evaluation of miRNA-related polymorphisms would provide useful information for personalized medicine. Utilizing miRNAs opens a new era in the fields of drug metabolism and pharmacokinetics as well as toxicology.

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“…In many laboratories, miRNAs have been shown to affect DMEs related with paracetamol metabolism (13)(14)(15)(16)(17)(18)(19). For example, miR-27b and miR-378 regulate paracetamol oxidation enzyme CYP3A4 and CYP2E1, respectively (13,14). Research on miRNAs regulation of phase II enzymes was limited to SULT1A1 (paracetamol sulfation enzyme), GSTP1 (NAPQI conjugation enzyme) and UGT1A (paracetamol glucuronidation enzyme) (15)(16)(17).…”

mentioning

confidence: 99%

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confidence: 99%

miRNA-324, a potential therapeutic target for paracetamol-induced liver injury

Kim

2016

Stem Cell Investig.

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Paracetamol is one of the most widely used medications for relieving pain and fever. When taken in the therapeutic doses, paracetamol is predominantly metabolized in the liver via conjugation reaction by phase II drug metabolizing enzymes such as sulfotransferases and glucuronyl transferases, and is removed from the body without liver damage (1). However, when paracetamol is taken in excessive doses, it is bioactivated by phase I enzymes (e.g., CYP3A4 and CYP2E1) to generate a toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI). Rapid generation of NAPQI can lead to the depletion of intrahepatic glutathione and result in hepatocyte death and liver injury (2). Thus, hepatotoxicity elicited by paracetamol overdose is the most common cause of poisoning-related deaths (3). In other studies, overdose of paracetamol accounted for the highest proportion of cases of acute liver failure in many developed countries, resulting in death or liver transplantation (4,5). Currently, N-acetylcysteine (NAC) is the mainstay strategy in treating hepatotoxicity following paracetamol overdose. However, oral and intravenous NAC treatment has limitations because of adverse effects (6,7). Thus, identifying new therapeutic targets would be of help for clinical remedy of paracetamol overdose-related liver injury.Numerous studies have been conducted on the expression and function of drug-metabolizing enzymes (DMEs), and the information was applied for better understanding and prediction of drug responses in patients (8). Moreover, identification of novel regulators of DMEs is critical to supply more information for clinical applications. In a recent issue of Stem Cells Transl Med, Hay and colleagues have identified that inhibition of a novel noncoding RNA can reduce paracetamol-induced liver toxicity (9). The authors demonstrated that miRNA-324-5p regulates phase II drug metabolism and that the inhibitor of miRNA-324-5p can promote nontoxic metabolism of paracetamol. This finding has the potential to help clinical research in identifying future therapeutic strategy for paracetamolinduced toxicity.To examine hepatocyte biology in vitro, immortalized human hepatocytes have been developed since they are the most physiologically relevant to human liver in drug response (10). However, some limitations such as karyotypic instability and poor function exist in the derived cell lines, thus preventing their further application (10). Previously, Hay et al. have used human embryonic stem cells (hESCs) to generate human hepatocyte-like cells (hHLCs) using a serum-free-based procedure (11), which has been proved to be scalable and more primary in nature and is promising in modeling human drug metabolism and toxicity. In the current research, according to the established methodology, hESCs were differentiated to hHLCs through 18 days of culture, as indicated by the appropriate cell morphology, gene expression, and appreciable levels of metabolic function (9). Hay et al. compared hHLCs with adult human hepatocytes and confirmed the gene expression p...

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MicroRNAs Regulate CYP3A4 Expression via Direct and Indirect Targeting

Cited by 236 publications

References 29 publications

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

MicroRNAs from biology to future pharmacotherapy: Regulation of cytochrome P450s and nuclear receptors

miRNA-324, a potential therapeutic target for paracetamol-induced liver injury

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