TY - JOUR
AU - Nakajima,, Miki
AB - Abstract MicroRNAs (miRNAs) are a large family of non-coding RNAs that are evolutionarily conserved, endogenous, and 21–23 nucleotides in length. miRNAs regulate gene expression by targeting messenger RNAs (mRNAs) by binding to complementary regions of transcripts to repress their translation or mRNA degradation. miRNAs are encoded by the genome, and more than 1000 human miRNAs have been identified so far. miRNAs are predicted to target ∼60% of human mRNAs and are expressed in all animal cells and have fundamental roles in cellular responses to xenobiotic stresses, which affect a large range of physiological processes such as development, immune responses, metabolism, tumor formation as well as toxicological outcomes. Recently, many reports concerning miRNAs related to cancer have been published; however, the miRNA research in the metabolism of xenobiotics and endobiotics and in toxicology has only recently been established. This review describes the current knowledge on the miRNA-dependent regulation of drug-metabolizing enzymes and nuclear receptors and its potential toxicological implications. In this review, miRNAs with reference to target prediction, potential modulation of toxicology-related changes of miRNA expression, role of miRNA in immune-mediated drug-induced liver injury, miRNA in plasma as potential toxicological biomarkers, and relevance of miRNA-related genetic polymorphisms are discussed. microRNA, miRNA, P450, CYP, posttranscriptional regulation, toxicology, polymorphism MicroRNAs (miRNAs) are short (∼22 to 25 nucleotides in length), single-stranded RNA genes possessing the reverse complement of the messenger RNA (mRNA) transcript of another protein-coding gene. miRNA was first found in Caenorhabditis elegans as RNA molecules that are complementary to the 3′ untranslated regions (UTRs) of the target transcript, such as lin-4 (Lee et al., 1993) and let-7 (Lau et al., 2001) genes. The development of the C. elegans was regulated by their respective targets. The miRNAs demonstrated diverse expression patterns during development and were found in diverse organisms, ranging from worms to humans (Lagos-Quintana et al., 2003), suggesting that these molecules represent a gene family that has evolved from an ancient ancestral small RNA gene. For nomenclature, miRNAs are assigned sequential numerical identifiers. The gene names are intended to convey limited information about functional relationships between mature miRNAs (Griffiths-Jones et al., 2006). For example, has-miR-101 in human and mmu-miR-101 in mouse are orthologous, and more than half of the known miRNAs are conserved across vertebrate animals (Lagos-Quintana et al., 2003). Paralogous sequences whose mature miRNAs differ at only one or two positions are given lettered suffixes, such as miR-10a and miR-10b. Distinct hairpin loci that give rise to identical mature miRNAs have numbered suffixes, such as miR-281-1 and miR-281-2. The passenger strand, named miRNA*, is usually degraded, although it is sometimes functional. The single strand form of mature miRNA is selectively loaded onto the RNA-induced silencing complex, composed of RNase III Dicer, TAR RNA-binding protein, and Argonaute protein Ago2 and guides the complex to its mRNA targets with imperfect pairing causing cleavage or translational repression of targeted mRNAs resulting in gene silencing (Bartel, 2004). Mechanisms for gene regulation and biogenesis of miRNAs have been described in detail in other review articles (Chekulaeva and Filipowicz, 2009; Choudhuri 2010; Fabian et al., 2010). In silico prediction estimates that ∼60% of human mRNAs could be targets of miRNAs (Friedman et al., 2009). Similar to mRNA, miRNA are expressed in a tissue- or cell-specific manner. miRNAs can potentially regulate every aspect of cellular processes such as differentiation, proliferation, apoptosis, and necrosis as well as a large range of physiological processes (Kloosterman and Plasterk, 2006). There is a growing body of research on the role of miRNAs in toxicogenomics/toxicogenetics and the possibility of drug-induced adverse effects. Because most drugs and chemical toxicants are biotransformed to exhibit their functions, the expression of drug- and xenobiotic-metabolizing enzymes and their regulation by miRNA is a potentially important determinant of the efficacy and toxicity. Although miRNA research in the metabolism of xenobiotics/endobiotics and in toxicology is still in its infancy, understanding of miRNAs is progressing rapidly. The purpose of this review is to summarize recent findings concerning the roles of miRNA in the regulation of cytochrome P450 (P450, CYP) and nuclear receptors and consider their potential relevance and application for toxicological studies. IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF miRNA TARGET GENE Computational identification of miRNA target genes is challenging because miRNA bind to the target mRNA with partial complementarity over a short sequence. The 5′-region of miRNA of six to seven nucleotides is called the “seed sequence”, and the 3′-mismatch is called the tolerant region (Mishra and Bertino, 2009). The seed sequence is critical and sometimes sufficient to repress the target translation (Lewis et al., 2003). A number of freely accessible and useful miRNA database are available as summarized in Table 1. Several computational algorithms such as MiRanda (John et al., 2004), TargetScan (Lewis et al., 2003), and PicTar (Krek et al., 2005) are also available to identify putative binding sites of miRNA to the target genes. A general algorithm to predict the target gene of miRNA has not been established, such that each in silico program can lead to different results due to the variable weight placed on the complementarity to the miRNA seed sequence, evolutionary conservation of the miRNA recognition element (MRE) of the target gene, free energy of the miRNA-mRNA duplex binding, and accessibility of the target site. Presently, the false-positive rate of the predicted candidate targets of a given miRNA is thought to be 30–50% (Alexiou et al., 2009; Watanabe et al., 2007), although additional enrichment analysis would help identify the most promising candidates (Hu et al., 2007). TABLE 1 InSilico Programs for the Prediction of miRNA Targets DIANA microT http://diana.cslab.ece.ntua.gr/microT/ EMBL-Target Gene Prediction http://www.russelllab.org/miRNAs/ MicroCosm http://www.ebi.ac.uk/enrightsrv/microcosm/htdocs/ MicroRNAdb http://bioinfo.au.tsinghua.edu.cn/micrornadb/ miRanda http://www.microrna.org/microrna/home.do miRBase http://microrna.sanger.ac.uk/ miRGator http://genome.ewha.ac.kr/miRGator/ mirnaviwer http://cbio.mskcc.org/mirnaviewer/ miRWalk http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/ PicTar http://pictar.org/ PITA http://genie.weizmann.ac.il/pubs/mir07/index.html RNA22 http://cbcsrv.watson.ibm.com/rna22.html RNAhybrid http://bibiserv.techfak.uni-bielefeld.de/rnahybrid/ TargetRank http://hollywood.mit.edu/targetrank/ TargetScan http://www.targetscan.org/ DIANA microT http://diana.cslab.ece.ntua.gr/microT/ EMBL-Target Gene Prediction http://www.russelllab.org/miRNAs/ MicroCosm http://www.ebi.ac.uk/enrightsrv/microcosm/htdocs/ MicroRNAdb http://bioinfo.au.tsinghua.edu.cn/micrornadb/ miRanda http://www.microrna.org/microrna/home.do miRBase http://microrna.sanger.ac.uk/ miRGator http://genome.ewha.ac.kr/miRGator/ mirnaviwer http://cbio.mskcc.org/mirnaviewer/ miRWalk http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/ PicTar http://pictar.org/ PITA http://genie.weizmann.ac.il/pubs/mir07/index.html RNA22 http://cbcsrv.watson.ibm.com/rna22.html RNAhybrid http://bibiserv.techfak.uni-bielefeld.de/rnahybrid/ TargetRank http://hollywood.mit.edu/targetrank/ TargetScan http://www.targetscan.org/ Open in new tab TABLE 1 InSilico Programs for the Prediction of miRNA Targets DIANA microT http://diana.cslab.ece.ntua.gr/microT/ EMBL-Target Gene Prediction http://www.russelllab.org/miRNAs/ MicroCosm http://www.ebi.ac.uk/enrightsrv/microcosm/htdocs/ MicroRNAdb http://bioinfo.au.tsinghua.edu.cn/micrornadb/ miRanda http://www.microrna.org/microrna/home.do miRBase http://microrna.sanger.ac.uk/ miRGator http://genome.ewha.ac.kr/miRGator/ mirnaviwer http://cbio.mskcc.org/mirnaviewer/ miRWalk http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/ PicTar http://pictar.org/ PITA http://genie.weizmann.ac.il/pubs/mir07/index.html RNA22 http://cbcsrv.watson.ibm.com/rna22.html RNAhybrid http://bibiserv.techfak.uni-bielefeld.de/rnahybrid/ TargetRank http://hollywood.mit.edu/targetrank/ TargetScan http://www.targetscan.org/ DIANA microT http://diana.cslab.ece.ntua.gr/microT/ EMBL-Target Gene Prediction http://www.russelllab.org/miRNAs/ MicroCosm http://www.ebi.ac.uk/enrightsrv/microcosm/htdocs/ MicroRNAdb http://bioinfo.au.tsinghua.edu.cn/micrornadb/ miRanda http://www.microrna.org/microrna/home.do miRBase http://microrna.sanger.ac.uk/ miRGator http://genome.ewha.ac.kr/miRGator/ mirnaviwer http://cbio.mskcc.org/mirnaviewer/ miRWalk http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/ PicTar http://pictar.org/ PITA http://genie.weizmann.ac.il/pubs/mir07/index.html RNA22 http://cbcsrv.watson.ibm.com/rna22.html RNAhybrid http://bibiserv.techfak.uni-bielefeld.de/rnahybrid/ TargetRank http://hollywood.mit.edu/targetrank/ TargetScan http://www.targetscan.org/ Open in new tab Confirmation and validation of the specific miRNA-mRNA interaction is most commonly addressed using luciferase reporter gene assays containing the MRE of the target downstream of the reporter gene. The constructs are cotransfected into cells with precursor miRNA (or the expression plasmid of miRNA) or antisense oligonucleotide for miRNA to overexpress or inhibit miRNA, and the reporter activity will establish whether the response is significantly decreased or increased compared with control. However, with reporter-based assays, it is necessary to examine whether the observed regulation would occur with the full-length UTR or whether other endogenous miRNAs regulate the candidate gene of interest. The overexpression and inhibition of miRNA are effective methods for determining the effects of miRNA on the target gene expression and understanding the biological function of miRNA. However, in overexpression experiments, a possible concern is that the concentration of miRNA may exceed physiological levels in the cells due to saturation of nuclear karyopherin exportin-5 resulting in potential aberrant cellular functions. The adverse effect of oversaturating endogenous small RNA pathways can be minimized by optimizing dose and sequence. In addition to the above direct methods, it is useful to determine the change of target mRNA or protein expression by microarray or proteome analysis after the overexpression and/or inhibition of miRNA (Beak et al., 2008; Lim et al., 2005). However, some caution is also required when using whole genomic or proteomic data because these platforms may also identify secondary targets, the expression of which may change as a result of changes in the expression of the primary targets. In this review, we highlight the state of science regarding the potential roles for miRNAs in the regulation genes involved in xenobiotic metabolism, nuclear receptors, genetic polymorphisms, and broad toxicologic responses. The emerging field of miRNAs as potential biomarkers of toxicity is also presented. A summary of the miRNAs discussed herein is provided in Table 2. TABLE 2 Nuclear Receptors and Drug Metabolizing Enzymes-Related MicroRNAs Target miRNA Reference PXR miR-148a Takagi et al. (2008) VDR miR-125b Mohri et al. (2009) miR-27b Pan et al. (2009) PPARα miR-21, miR-27b Kida et al. (2011) PPARγ miR-27a Kim et al. (2010),Lin et al. (2009) miR-27b Karbiener et al. (2009) miR-130 Lee et al. (2010) RXRα (rat) miR-27 Ji et al. (2009) HIF-1α miR-17 Taguchi et al. (2008) HNF4α miR-24a, miR-34 Takagi et al. (2010) ERα miR-206 Adams et al. (2007) miR-221/222 Zhao et al. (2008) miR-22 Xiong et al. (2010) GR miR-18, miR-124a Vreugdenhil et al. (2009) CYP1B1 miR-27b Tsuchiya et al. (2006) CYP2A3 (rat) miR-126* Kalsheuer et al. (2008) CYP2E1 miR-378 Mohri et al. (2010) CYP3A4 miR-27b Pan et al. (2009a) CYP24A1 miR-125b Komagata et al. (2009) DHFR miR-24 Mishra et al. (2007) SULT1A1 miR-631 Yu et al. (2010) Thioredoxin reductase miR--298, miR-370 Fukushima et al. (2007) Mitochondrial antioxidant enzymes miR-17* Xu et al. (2010) Target miRNA Reference PXR miR-148a Takagi et al. (2008) VDR miR-125b Mohri et al. (2009) miR-27b Pan et al. (2009) PPARα miR-21, miR-27b Kida et al. (2011) PPARγ miR-27a Kim et al. (2010),Lin et al. (2009) miR-27b Karbiener et al. (2009) miR-130 Lee et al. (2010) RXRα (rat) miR-27 Ji et al. (2009) HIF-1α miR-17 Taguchi et al. (2008) HNF4α miR-24a, miR-34 Takagi et al. (2010) ERα miR-206 Adams et al. (2007) miR-221/222 Zhao et al. (2008) miR-22 Xiong et al. (2010) GR miR-18, miR-124a Vreugdenhil et al. (2009) CYP1B1 miR-27b Tsuchiya et al. (2006) CYP2A3 (rat) miR-126* Kalsheuer et al. (2008) CYP2E1 miR-378 Mohri et al. (2010) CYP3A4 miR-27b Pan et al. (2009a) CYP24A1 miR-125b Komagata et al. (2009) DHFR miR-24 Mishra et al. (2007) SULT1A1 miR-631 Yu et al. (2010) Thioredoxin reductase miR--298, miR-370 Fukushima et al. (2007) Mitochondrial antioxidant enzymes miR-17* Xu et al. (2010) Open in new tab TABLE 2 Nuclear Receptors and Drug Metabolizing Enzymes-Related MicroRNAs Target miRNA Reference PXR miR-148a Takagi et al. (2008) VDR miR-125b Mohri et al. (2009) miR-27b Pan et al. (2009) PPARα miR-21, miR-27b Kida et al. (2011) PPARγ miR-27a Kim et al. (2010),Lin et al. (2009) miR-27b Karbiener et al. (2009) miR-130 Lee et al. (2010) RXRα (rat) miR-27 Ji et al. (2009) HIF-1α miR-17 Taguchi et al. (2008) HNF4α miR-24a, miR-34 Takagi et al. (2010) ERα miR-206 Adams et al. (2007) miR-221/222 Zhao et al. (2008) miR-22 Xiong et al. (2010) GR miR-18, miR-124a Vreugdenhil et al. (2009) CYP1B1 miR-27b Tsuchiya et al. (2006) CYP2A3 (rat) miR-126* Kalsheuer et al. (2008) CYP2E1 miR-378 Mohri et al. (2010) CYP3A4 miR-27b Pan et al. (2009a) CYP24A1 miR-125b Komagata et al. (2009) DHFR miR-24 Mishra et al. (2007) SULT1A1 miR-631 Yu et al. (2010) Thioredoxin reductase miR--298, miR-370 Fukushima et al. (2007) Mitochondrial antioxidant enzymes miR-17* Xu et al. (2010) Target miRNA Reference PXR miR-148a Takagi et al. (2008) VDR miR-125b Mohri et al. (2009) miR-27b Pan et al. (2009) PPARα miR-21, miR-27b Kida et al. (2011) PPARγ miR-27a Kim et al. (2010),Lin et al. (2009) miR-27b Karbiener et al. (2009) miR-130 Lee et al. (2010) RXRα (rat) miR-27 Ji et al. (2009) HIF-1α miR-17 Taguchi et al. (2008) HNF4α miR-24a, miR-34 Takagi et al. (2010) ERα miR-206 Adams et al. (2007) miR-221/222 Zhao et al. (2008) miR-22 Xiong et al. (2010) GR miR-18, miR-124a Vreugdenhil et al. (2009) CYP1B1 miR-27b Tsuchiya et al. (2006) CYP2A3 (rat) miR-126* Kalsheuer et al. (2008) CYP2E1 miR-378 Mohri et al. (2010) CYP3A4 miR-27b Pan et al. (2009a) CYP24A1 miR-125b Komagata et al. (2009) DHFR miR-24 Mishra et al. (2007) SULT1A1 miR-631 Yu et al. (2010) Thioredoxin reductase miR--298, miR-370 Fukushima et al. (2007) Mitochondrial antioxidant enzymes miR-17* Xu et al. (2010) Open in new tab ROLE OF miRNAs IN REGULATING NUCLEAR RECEPTORS AND ENZYMES THAT METABOLIZE XENOBIOTICS/ENDOBIOTICS The expression of drug- and xenobiotic-metabolizing enzymes and nuclear receptors and their regulation by miRNA could be important factors for the outcomes of toxicity. Members of the cytochrome P450 (P450, CYP) family are the most important enzymes catalyzing the metabolism of xenobiotics including drugs, environmental chemicals, and carcinogens. The different profiles of the expression of P450 isoenzymes determine the amount of reactive intermediates formed and the resulting toxic response. P450s are also known to bioactivate many procarcinogens to their ultimate carcinogens. Whereas the mechanisms of the transcriptional regulation of P450-related nuclear receptors have been well studied, the posttranscriptional regulation largely remains unknown. Recently, some P450s and nuclear receptors have been found to be posttranscriptionally regulated by miRNAs and are summarized herein. Human CYP1B1 Human CYP1B1, expressed mainly in ovary, uterus, and breast (Shimada et al., 1996; Sutter et al., 1994), catalyzes the metabolic activation of a variety of procarcinogens and promutagens, including polycyclic aromatic hydrocarbons and aryl amines , and the metabolism of 17β-estradiol (Hayes et al., 1996; Lee et al., 2003; Spink et al., 1997), which contributes to the growth and development of estrogen-dependent cancers such as breast and endometrial cancers (Henderson and Canellos, 1980). 4-Hydroxyestradiol, a catechol-type metabolite formed by CYP1B1, generates free radicals from reductive-oxidative cycling with the corresponding semiquinone and quinone forms, which cause DNA damage (Han and Liehr, 1994; Newbold and Liehr, 2000). It should be noted that there is no apparent difference in the CYP1B1 mRNA levels between tumor and normal tissues (Cheung et al., 1999; Ragavan et al., 2004), whereas the expression of CYP1B1 protein and its enzymatic activity is much higher in various types of malignant cancers compared with normal tissues (Murray et al., 1997). Posttranslational regulation of human CYP1B1 expression was suggested to result from polymorphism-dependent degradation of CYP1B1 protein by polyubiquitination but not phosphorylation (Bandiera et al., 2005). The first study to demonstrate that miRNA can regulate any CYP was reported for human CYP1B1. Specifically, human CYP1B1, which is highly expressed in estrogen target tissues (Tsuchiya et al., 2004), is regulated by miR-27b in MCF-7 breast cancer cells (Tsuchiya et al., 2006). Exogenously expressed miR-27b decreases the luciferase reporter activity in Jurkat cells (miR-27 negative). In MCF-7 cells (miR-27 positive), an antisense oligonucleotide to miR-27b restored the luciferase reporter activity and increased the protein level and enzymatic activity of endogenous CYP1B1 (Tsuchiya et al., 2006). These lines of evidence strongly suggest that human CYP1B1 is posttranscriptionally regulated by miR-27b. Extending the work to breast cancer patients, the expression of miR-27b was decreased in most patients and that of CYP1B1 protein was increased in 24 cancerous tissues compared with noncancerous tissues (p < 0.0005) in each patient. Because miR-27b targets CYP1B1 mRNA, the decreased expression of miR-27b is one of the causes of the high expression of CYP1B1 protein. Furthermore, although 4-hydroxylation of estrogen by CYP1B1 decreases estrogenic activity, this metabolite is toxicologically active. Accordingly, miR-27b levels may contribute to estrogen-dependent molecular mechanisms of carcinogenesis. Human CYP3A4 and Pregnane X Receptor Human CYP3A4 is the most important CYP enzyme in facilitating the metabolism and elimination of a wide range of structurally different xenobiotics including more than 50% of all clinically relevant drugs (Bertz and Granneman, 1997). The CYP3A4 phenotype has been assessed using several substrates (e.g., midazolam and erythromycin), which revealed that there is at least sixfold interindividual variation of the activities in most populations (Floyd et al. 2003; Lin et al., 2002; Rodriguez-Antona et al., 2005), and this population variability cannot be explained solely by genetic polymorphisms (Floyd et al., 2003; Lamba et al., 2002). CYP3A4 expression is largely regulated at the transcriptional level by transcriptional factors, such as CCAAT/enhancer binding proteins, C/EBPα and C/EBPβ, and hepatocyte nuclear factors, hepatocyte nuclear factor 4α (HNF4α) and HNF3γ, as well as constitutive androstane receptor (CAR) and pregnane X receptor (PXR) (Martinez-Jimenez et al., 2007). Animal and human CYP3A enzymes are also involved in the metabolic activation of several drugs and xenobiotics to toxic metabolites (Thummel et al., 1993). Human hepatocytes are ideal for in vitro cytotoxicity screening assays, but their overall utility is hampered by large interindividual variability of enzyme activity. A highly sensitive cell-based screening method for CYP3A4-dependent metabolic activation using HepG2 cells was demonstrated, and with this method, the cytotoxicity of drugs was efficiently evaluated (Hosomi et al., 2010, 2011). Notably, aflatoxin B1 and G1 and benzo[a]pyrene (BaP) are known to be oxidized efficiently to genotoxic metabolite(s) by CYP3A (Forrester et al., 1990; Shimada et al., 1989). The role of miRNA in the regulation of the expression of CYP3A4 has been reported (Takagi et al., 2008). In a panel of 25 human livers, PXR mRNA level was not correlated with PXR protein, suggesting the involvement of posttranscriptional regulation. However, no involvement of miRNAs was suggested in CYP3A4 by the correlation analyses between the CYP3A4 mRNA level and CYP3A4 protein level. In contrast, a potential miR-148a recognition element was identified in the 3′-UTR of human PXR mRNA. A reporter assay revealed that miR-148a could recognize the miR-148a recognition element of PXR mRNA. Consequently, overexpression of miR-148a resulted in a reduction of the PXR protein, whereas inhibition of miR-148a by using antisense oligonucleotides increased the PXR protein level. The miR-148a-dependent decrease of PXR protein attenuated the induction and/or constitutive levels of CYP3A4 mRNA. Furthermore, the translational efficiency of PXR (PXR protein/PXR mRNA ratio) was inversely correlated with the expression levels of miR-148a in a panel of human livers. Actually, a potential miR-148a recognition element in the 3′-UTR of human CYP3A4 mRNA did not regulate CYP3A4 message level. There is one literature report that CYP3A4 protein in LS180 and human pancreas cancer-derived PANC1 cells was decreased by the overexpression of miR-27b, a result accompanied by a decrease of the CYP3A4 mRNA level (Pan et al., 2009). In that report, only the overexpression of miR-27b was evaluated, and ideally, the results from inhibiting endogenous miRNA as well as a correlation analysis between the miRNA and target mRNA levels are necessary to fully evaluate the potential regulation of miRNAs. It has also been shown that PXR protein levels were not significantly correlated with CYP2B6 or MDR1 mRNA levels in the panel of human livers. Thus, it was speculated that the PXR level does not largely affect the constitutive expression of CYP2B6 and MDR1 in the liver. In an induction study, the induction of CYP2B6 (twofold) and MDR1 (fivefold) mRNA by rifampicin in LS180 cells was attenuated by the overexpression of miR-148a (Takagi et al., 2008). Therefore, the new information was provided that the miR-148a posttranscriptionally regulated human PXR resulting in the modulation of the inducible and/or constitutive levels of CYP3A4 in human liver. This study suggested a new miRNA-dependent mechanism in the large interindividual variability of CYP3A4 expression via PXR expression in human. Human CYP2E1 Human CYP2E1 is a pharmacologically and toxicologically important P450 isoform. Human CYP2E1 catalyzes the metabolism of numerous low molecular weight xenobiotics including drugs (e.g., acetaminophen, isoniazid, and brombenzene), organic solvents (e.g., ethanol, acetone, carbon tetrachloride, chloroform, vinyl chloride, glycerol, hexane, and toluene), and procarcinogens (e.g., N-nitrosodimethylamine, N-nitrosomethylethylamine, and N-nitrosopyrrolidine) (Lu and Cederbaum, 2008). CYP2E1 is induced by its own substrates such as isoniazid, ethanol, and acetone and enhances their metabolism (Bolt et al., 2003). In addition, CYP2E1 is the most abundant isoform among all P450s in human liver (56% of total P450) at the mRNA level, followed by CYP2C9, CYP2C8, and CYP3A4 (8–11% of total P450) (Bieche et al., 2007), whereas it is the fourth most abundant isoform (about 7% of total P450) at the protein level after CYP3A (30% of total P450), CYP2C (20% of total P450), and CYP1A2 (about 13% of total P450) (Shimada et al., 1994). Collectively, posttranscriptional regulation may contribute to the constitutive and inducible expression of CYP2E1 in human liver. The potential for miRNAs to function in the posttranscriptional regulation of human CYP2E1 was studied after in silico analysis identified a potential recognition element of miR-378 (MRE378) in the 3′-UTR of human CYP2E1 mRNA (Mohri et al., 2010). Luciferase assays using HEK293 cells confirmed that miR-378 functionally recognized MRE378. Two HEK293 cell lines stably expressing human CYP2E1 including or excluding the 3′-UTR were established. When the precursor miR-378 was transfected into the cells expressing human CYP2E1 including 3′-UTR, the CYP2E1 protein level and chlorzoxazone 6-hydroxylase activity (marker activity of CYP2E1) were significantly decreased but not in the cells expressing CYP2E1 excluding 3′-UTR. Unexpectedly, in both cell lines, the CYP2E1 mRNA levels were decreased by overexpression of miR-378, but miR-378 did not affect the stability of CYP2E1 mRNA. Therefore, the down-regulation of CYP2E1 by miR-378 appears to be due to the translational repression rather than mRNA degradation. In a panel of 25 human livers, no positive correlation was observed between the CYP2E1 protein and CYP2E1 mRNA levels, supporting the posttranscriptional repression. Interestingly, the miR-378 levels were inversely correlated with the CYP2E1 protein levels and the translational efficiency (protein/mRNA expression ratio) of human CYP2E1. It is important to note that the 3′-UTR of CYP2E1 is poorly conserved among human, rat, and mouse. As a result, the regulation of CYP2E1 by miR-378 may be specific to humans. In addition to its role in CYP2E1 expression, miR-378 promotes cell survival, tumor growth, and angiogenesis by repressing the expression of Sufu (suppressor of fused) and Fus-1 (one of the oxygen-binding functional units within KLH), which are tumor suppressors (Lee et al., 2007). Furthermore, miR-378 binds to the 3′-UTR of vascular endothelial growth factor (VEGF) and promotes expression of VEGF (Hua et al., 2006). The expression of CYP2E1 is up-regulated in diabetes and obesity but down-regulated by insulin treatment (de Waziers et al., 1995; Wang et al., 2003; Woodcroft et al., 2002). Thus, the involvement of miR-378 in the induction of CYP2E1 by chemicals/xenobiotics along with its role in cell growth and metabolic disease is likely to be toxicologically significant. Rat CYP2A3 CYP2A3 has been isolated from a rat lung cDNA library and is expressed in lung but not in liver, kidney, or small intestines (Kimura et al., 1989). 3-Methylcholanthrene increases lung CYP2A3 levels by ∼threefold, whereas phenobarbital is not an inducer of CYP2A3 gene expression. In lung, CYP2A3 is a principal catalyst of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) α-hydroxylation, the primary bioactivation pathway for NNK (Jalas et al., 2005). The chronic administration of NNK to F344 rats reduced the expression of several miRNAs including miR-126* and miR-34 in lung (Kalscheuer et al., 2008). The passenger strand, named miRNA*, is usually degraded, although it is sometimes functional. It was found that CYP2A3 is regulated by the miR-126*. Because the reduced miR-126* expression was accompanied by increased CYP2A3 expression (both mRNA and protein levels) in the NNK-treated rats, these expression changes were thought to reinforce NNK genotoxicity. The reduced expression of miR-34 observed after NNK exposure is also noteworthy because it is reported to be involved in the regulation of a tumor suppressor p53 (Corney et al., 2007; He et al., 2007). However, p53 mRNA expression did not change in NNK-treated rats (Kalscheuer et al., 2008). HUMAN CYP24A1 AND VITAMIN D RECEPTOR Human CYP24A1 is an essential enzyme involved in the inactivation of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3; calcitriol]. Calcitriol, a biologically active metabolite of vitamin D3, is typically considered a regulator of calcium homeostasis, but it has now received much interest for its antitumor activity (Deeb et al., 2007: Nagpal et al., 2005). CYP24A1 has been reported to be overexpressed in various tumor cells (Deeb et al., 2007). Although there is some controversy about the expression of CYP24A1 mRNA and protein in cancer tissues compared with those in noncancerous tissue due to the heterogeneous background in different breast cancers (de Lyra et al., 2006; Hicks et al., 2006; Townsend et al., 2005), the overexpression of CYP24A1 protein is not necessarily associated with the increased CYP24A1 mRNA level. Most of the biological effects of calcitrol are elicited by its binding to vitamin D receptor (VDR) (Carlberg and Polly, 1998). Calcitrol has been associated with the risk of cancer (Garland et al., 2006). Because the vitamin D system has relevance for both the prevention and treatment of cancer (Holick, 2007), the development of a number of novel synthetic vitamin D analogues as a therapeutic agent for cancer has been attempted. It has been reported that, at the protein level, the VDR expression is higher in breast (Friedrich et al., 2002) and thyroid (Khadzkou et al., 2006) cancers than in normal tissues, but no difference was found between cancer and normal tissues at the mRNA level, suggesting the involvement of posttranscriptional regulation. It was reported that both human CYP24A1 (Komagata et al., 2009) and VDR (Mohri et al., 2009) are posttranscriptionally regulated by miR-125b. A potential miR-125b recognition element (MRE125b) in the 3′-UTR of human CYP24A1 and VDR mRNA was functional to these target proteins. The CYP24A1 protein levels in cancer tissues were inversely associated with the cancer/normal ratios of the miR-125b levels, suggesting that the decreased miR-125b levels in breast cancer tissues may contribute to the high CYP24 protein expression. Because CYP24A1 is a target of VDR, miR-125b may directly and/or indirectly regulate the CYP24A1. An increase of VDR in cancer tissues would augment the antitumor effects of calcitrol, whereas an increase of CYP24A1 would attenuate the antitumor effects. The role of miR-125b relative to the antiproliferative effects of calcitrol was studied in MCF-7 cells, wherein it was shown that miR-125b increased cell growth. These results indicate that miR-125b is a part of VDR downstream activities. In other studies, miR-125b inhibited proliferation of human hepatocellular carcinoma cells (Li et al., 2008), thyroid carcinoma cells (Visone et al., 2007), and human breast cancer cells (Scott et al., 2007). In contrast, inhibition of miR-125b decreased growth of human prostate cancer cells (Lee et al., 2005). Importantly, miR-125b expression is differentially affected in various human tumors, with evidence for being down-regulated in breast, ovarian, and bladder cancers, whereas its expression is up-regulated in pancreas and stomach cancers (Volinia et al., 2006). Thus, the functional effects of miR-125b differ in each cancerous tissue. There is presently considerable interest in evaluating miR-125b as a potential biomarker of cancer-related outcomes, but more research is needed. Human HNF4α and Bile Acid Toxicity Human HNF4α, which belongs to the nuclear hormone receptor superfamily, is highly expressed in liver, and to a lesser degree in kidney, small intestine, and colon and regulates the expression of various genes involved in the synthesis/metabolism of bile acid, fatty acid, cholesterol, glucose, and urea as well as hepatocyte differentiation (Gonzalez, 2008). It is well recognized that endo/xenobiotic-metabolizing enzymes such as CYPs, UGTs, and sulfotransferase are under the control of HNF4α (Kamiyama et al., 2007). HNF4α transactivates the expression of target genes not only via direct binding to their regulatory sequences but also through the regulation of other transcriptional factors such as PXR and CAR, which regulate these target genes. HNF4α forms large transcriptional regulatory networks in the liver. Potential recognition elements for miR-24 (MRE24) were identified in the coding region and the 3′-UTR of HNF4α, whereas miR-34a (MRE34a) recognition elements were identified in only the 3′-UTR of HNF4α mRNA (Takagi et al., 2010). HNF4α protein levels in HepG2 cells were markedly decreased by overexpression of miR-24 and miR-34a, and HNF4α mRNA levels were significantly decreased by the overexpression of miR-24 but not by miR-34a. The luciferase reporter activity of plasmid containing the 3′-UTR of HNF4α was significantly decreased by miR-34a and that of plasmid containing the HNF4α coding region was significantly decreased by miR-24, suggesting that the MRE24 in the coding region and MRE34a in the 3′-UTR is functional in the negative regulation by mRNA degradation and translational repression, respectively. The down-regulation of HNF4α by these miRNAs resulted in the decrease of various target genes such as CYP7A1 and CYP8B1 as well as morphological changes and the decrease of the S phase population in HepG2 cells (Takagi et al., 2010). In addition, expression of miR-24 and miR-34a were regulated by protein kinase C/mitogen-activated protein kinase and reactive oxygen species pathways, respectively. It is well known that HNF4α positively regulates the expression of bile acid-synthesizing enzymes such as CYP7A1 and CYP8B1. CYP7A1 catalyzes the first and rate-limiting step in the bile acid synthetic pathway (Pikuleva, 2006). Therefore, induction of miR-24 and miR-34a is expected to decrease bile acid synthesis via mainly CYP7A1. In addition, the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) was also down-regulated by the decrease of HNF4α expression by miRNAs. Thus, miR-24 and miR-34a affect the various hepatic functions through the negative regulation of HNF4α expression (Takagi et al., 2010). ROLE OF miRNAs IN REGULATING OTHER NUCLEAR RECEPTORS Human Estrogen Receptor α Estrogen receptor α (ERα) is an important marker for the prognosis and is predictive of the response to endocrine therapy in breast cancer patients. Up to one third of the patients with breast cancer lack ERα at the time of diagnosis. It was previously reported that ERα regulates the expression of human CYP1B1, which catalyzes the metabolism of estradiol to the toxicologically active endogenous metabolite, 4-hydroxyestradiol (Tsuchiya et al., 2004). It was first demonstrated by Adams et al. (2007) that human ERα is regulated by miR-206, whereas the activation of ERα results in the decreased expression of miR-206, showing mutually inhibitory regulation. miR-221 and miR-222 also inhibit human ERα expression at the translational level (Xiong et al., 2010; Zhao et al., 2008). Expression of miR-22 and ERα protein were inversely associated and ERα is the primary target (Pandey and Picard, 2009). miR-375 was identified as a potential target of dexamethasone-induced Ras-related protein 1 (RASD1), and it was found that RASD1 negatively regulates ERα expression (Simonini et al., 2010). miR-27a indirectly regulates human ERα via ZBTB10, a specific protein repressor for Sp2, Sp3, and Sp4 (Li et al., 2010). From these lines of data, the authors suggested that a variety of miRNAs may be potential targets for anti-estrogen therapy. However, it should be noted that study-specific experimental conditions varied considerably as they were derived from cultured hepatoma cell lines, established cells from tumor tissues and/or tissue samples, and lacked quantitative consideration of the data. Thus, although these data offer the potential for potential treatment possibilities, more research is needed to establish causal relationships in this area. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS Peroxisome proliferator-activated receptor (PPAR) α is an important transcriptional factor that regulates genes encoding endo/xenobiotic enzymes and lipid-metabolizing enzymes. The overexpression and inhibition of miR-21 or miR-27b in HuH7 cells significantly decreased and increased the PPARα protein level, respectively, but not PPARα mRNA level (Kida et al., 2011). These miRNAs negatively regulate the expression of PPARα in human liver, and because PPARα is an important regulator of fatty acid catabolism, miR-21 and miR-27b may contribute to the regulation of lipid metabolism. In spite of the different experimental conditions in each research group, miR-27a and miR-27b were reported to be targets of PPARγ (Jennewein et al., 2010; Karbiener et al., 2009; Kim et al., 2010; Lin et al., 2009). Interestingly, the inhibition of miR-27b, induced by lipopolysaccharide (LPS), reversed PPARγ mRNA degradation. Whereas miR-27b overexpression decreased PPARγ mRNA, affecting the LPS-induced expression of the pro-inflammatory cytokines, tumor necrosis factor α and interleukin-6 (IL-6; Jennewein et al., 2010). The expression of miR-27a and miR-27b increased in fat tissue of obese mice and was regulated by hypoxia (Lin et al., 2009). miR-130 potently repressed PPARγ expression by targeting both the PPARγ mRNA coding and 3′-UTR regions, thereby controlling adipocyte gene expression programs (Lee et al., 2010). Retinoid X Receptor Retinoid X receptor (RXR) α has been shown to be a target of miR-27a and miR-27b in rat primary hepatic stellate cells (Ji et al., 2009). The sequences of MRE on the RXRα mRNA are highly conserved among species, suggesting that human RXRα may also be regulated by miR-27. RXRα is involved in multiple signaling pathways related to cell proliferation and differentiation, mainly as the heterodimeric partner of several nuclear receptors (Imai et al., 2001). Therefore, miR-27 seems to be involved in the regulation of a wide variety of transcriptional factors affecting inter- and intraindvidual differences in drug response, adverse reactions, and toxicity outcomes. In addition, as mentioned above, CYP1B1 is a direct target of human miR-27b (Tsuchiya et al., 2006). The review of miRNA regulation of CYP and nuclear receptor regulation demonstrates that miRNA regulatory networks are complex because a single miRNA can target numerous mRNAs, often in combination with other miRNAs and nuclear receptors, and a single target can be regulated by different kinds of miRNA (Fig. 1). As we learn more about this important research field, it is anticipated that miRNAs will be shown to contribute broadly to understanding mechanisms of toxicity and for predicting the risk susceptibility for drugs, chemical toxicants, and environmental pollutants. IN VITRO AND IN VIVO MODULATION OF TOXICOLOGY-RELATED miRNA EXPRESSION Although the precise roles of miRNA in the response to xenobiotics, drugs and chemical toxicants, remain to be established, there is little doubt that miRNAs are important in the cellular and in vivo responses to xenobiotics (Taylor and Gant, 2008). However, the regulatory networks of miRNAs are complex, and decreased expression of miRNAs will generally lead to high expression of the target proteins. In contrast, increased expression of miRNAs is less likely to be associated with toxicological phenomena. Comprehensive studies using miRNA arrays as well as DNA microarrays and proteomics analyses are powerful tools to investigate the mechanisms of individual susceptibility to toxicants and adverse drug reactions. Recently, a large number of studies on the roles of miRNAs in cancer have been investigated, but few studies have reported the altered expression profiles of miRNA in drug-related adverse reactions and in toxicology-related outcomes. There are numerous examples of the potential roles whereby miRNAs can influence toxic responses. Many of these have only been evaluated in vitro but are relevant to toxicology and disease development. For example, human miR-222 regulates matrix metalloproteinase 1 (MMP1) expression level through both direct cis-regulatory mechanisms (targeting MMP1 mRNA) and direct trans-regulatory mechanisms (indirect controlling of MMP1 gene expression by targeting superoxide dismutase-2 (SOD2) (Liu et al., 2009). SOD2-dependent up-regulation of MMPs may, at least in part, contribute to the increased invasion and metastatic capacity of tumors displaying elevated SOD2 levels. A significant observation from both in vitro and in vivo studies is that cigarette smoking causes the down-regulation of many miRNAs in the lungs of both mice and rats (Izzotti et al., 2011) as well as in human airway epithelial cells (Schembri et al., 2009). Finally, arsenite, which is known to activate nuclear factor-erythroid 2-related factor 2 (Nrf2) (Aono et al., 2003), affects miRNA expression in human lymphoblastoid TH-6 cells (Marsit et al. 2006), although the impact of such changes on toxicity is not yet known. It has also been demonstrated that miR-17* suppresses the primary mitochondrial antioxidant enzymes, such as SOD2, glutathione peroxidase-2 (GPX2), and thioredoxin reductase-2 (RXR2), in prostate cancer PC-3 cells (Xu et al., 2010). The luciferase reporter activities were suppressed by the overexpression of miR-17* and disulfiram, a dithiocarbamate drug, induced the expression level of mature miR-17*. It was previously reported that miR-17 is able to silence hypoxia-inducible factor-1α expression (Taguchi et al., 2008). From these reports, it is conceivable that the miR-17 and miR-17* might involve in maintaining the homeostasis against cellular redox stress. Several studies employing toxicogenomics have been carried out to evaluate the responses of miRNAs in rodent liver with the goal of identifying potential biomarker(s) for toxicological risk assessment. It was reported that single administration of acetaminophen or carbon tetrachloride to rats resulted in different expression profiles of miRNA in the liver (Fukushima et al., 2007). Changes in miRNA-298 and miR-370, which presumably target oxidative stress-related enzymes including thioredoxin reductases were noted. In this early work, the sample size was very small and no statistical analyses were conducted. However, miRNA suppression occurred as early as 6 h later, which coincided with the early phase toxicity, prior to cellular necrosis. It has also been demonstrated that let-7C, a miRNA important in cell growth, was inhibited with the potent PPARα agonist WY-14,643 in wild-type mice (Shah et al., 2007). In addition, let-7C was also shown to target c-myc via direct interaction with the 3′-untranslated region of c-myc, which subsequently increasing the expression of the oncogenic miR-17-92. Thus, a let-7C signaling cascade appears to be critical for PPARα agonist-induced liver proliferation. In interesting in vivo finding is that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) did not cause any potent changes in hepatic miRNA expression in TCDD-resistant H/W rats and TCDD-sensitive L-E rats (Moffat et al., 2007), and similar results were obtained in mice. The authors concluded that down-regulation of hepatic miRNA by TCDD is unlikely to play a significant role in TCDD toxicity in adult rodent liver. In addition, BaP3 (daily doses of 150 mg/kg) caused widespread changes in gene expression (>400 genes), but almost no changes in miRNA expression when evaluated by microarray analyses. Collectively, although miRNA expression would be co-ordinately regulated with the mRNA transcript, it is interesting that hepatic miRNA in vivo is not directly responsive to aryl hydrocarbon receptor (AHR)-agonists such as TCDD and BaP in vivo in rodents (Yauk et al., 2011). Concerning in vitro studies, cells treated with γ-irradiation showed no alteration in miRNA expression (Marsit et al., 2006). In contrast, when the human lymphoblast cell line IM9 was treated with γ-irradiation, various changes in miRNAs in a dose-dependent manner were noted (Cha et al., 2009). The conflicting data for γ-irradiation may be a function of cell types or experimental conditions used in these studies and need to be clarified. From these data, it is conceivable that there are different responses in miRNA changes between in vitro and in vivo, and an in vitro study alone may not able to predict the in vivo responses of miRNA for these kinds of toxic chemicals. Finally, chronic exposure to toxic chemicals in rodents can produce different results in miRNA expression profiles compared with acute toxicity studies. For example, it was reported that tamoxifen, a potent hepatocarcinogen in rats, caused statistically significant differential expression of 33 hepatic miRNAs (20 genes up-regulated; 13 genes down-regulated) when administered to Fisher 344 rats for 24 weeks (Pogribny et al., 2007). A significant up-regulation of oncogenic miRNAs, such as the miR-17-92 cluster, miR-106a, and miR-34, was observed. A number of miRNAs, including miR-152 and miR-195, were down-regulated in the livers of tamoxifen-treated rats. These miRNAs are frequently down-regulated in solid tumors (Murakami et al., 2006). In addition, the differential expression of 55 miRNAs (31 genes up-regulated; 25 genes down-regulated) in mice fed a diet containing hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a common environmental contaminant, at 5 mg/kg for 28 days (Zhang and Pan, 2009). A significant up-regulation of oncogenic miRNAs and a significant down-regulation of tumor-suppressing miRNAs, such as let-7, miR-17-92 cluster, miR-10b, miR-15, miR-16, miR-26, and miR-181, were observed. Thus, chronic administration of toxic chemicals will affect the changes of miRNA expression in the liver in vivo, which are different compared with those of acute administration. ROLE OF miRNA IN IMMUNE-MEDIATED DRUG-INDUCED LIVER INJURY Cytokines are recognized to decrease CYP-associated drug metabolism in humans during inflammation and infection (Abdel-Razzak et al., 1993), which influences the susceptibility to various drugs and toxic chemicals. IL-6 was demonstrated to decrease both the rifampicin- and phenobarbital-mediated induction of CYP2B6, CYP2C8, CYP2C9, and CYP3A4, whereas, the transcriptional activity of PXR and CAR is not affected by IL-6 (Pascussi et al., 2000). With respect to cytokines and drug-induced liver injury (DILI), halothane- and α-naphthylisothiocyanate-induced liver injury is reported to be mediated by IL-17 (Kobayashi et al., 2009, 2010), whereas IL-4 mediates dicloxacillin- and flutamide-induced liver injury in mice (Higuchi et al., 2011). Furthermore, IL-6 and IL-4 are essential for the differentiation of Th17 and Th2 cells, respectively, from naïve T cells. The generation of reactive metabolites by the administered drugs is catalyzed by P450s, which are suggested to be a major causal factor for the initiation of DILI, and thereafter, the exacerbation of DILI will be affected by ILs. In recent years, many studies have highlighted the fact that miRNAs play a critical role in the differentiation and function of the adaptive and innate immune system (Carissimi et al., 2009). Indeed, several studies demonstrated the involvement of ILs in relation to miRNA-related diseases and cancer as follows. The expression of miR-148a, miR-152, and miR-301 was decreased in IL-6-overexpressing malignant cholangocytes. IL-6 can increase the exprssion of DNA methyltransferase-1, which is a target of miR-148a and miR-152 (Braconi et al., 2010). The expression of bone morphogenic protein receptor type II (BMPR2) through an miR-17/92 pathway is modulated by IL-6. Because IL-6 signaling is mainly mediated by STAT3, the expression of STAT3 was knocked down by small interfering RNA, which abolished the IL-6-mediated expression of miR-17/92 (Brock et al., 2009). miR-21 contributes to the oncogenic potential of Stat 3 in multiple myeloma cells. miR-21 induction by IL-6 was strictly Stat 3 dependent through a highly conserved enhancer (Loffler et al., 2007). Six miRNAs, let-7a, miR-26, miR-146a/b, miR-150, and miR-155 were significantly up-regulated in the IL-17 producing T cells. miR-146a is associated with IL-17 expression in the peripheral blood mononuclear cells in rheumatoid arthritis patients (Niimoto et al., 2010). Interestingly, microRNA expression analysis during the tolerized state of THP-1 cells showed only miR-146a overexpression, suggesting its important role in LPS tolerance. Transfection of miR-146a into THP-1 cells mimicked LPS priming, whereas transfection of miR-146a inhibitor largely abolished LPS tolerance (Nahid et al., 2009). RELEVANCE OF miRNA-RELATED GENETIC POLYMORPHISM TO PHARMACOGENETICS/GENOMICS STUDIES The human genome contains about 3 billion base pairs, and single-base variations (called SNPs, single-nucleotide polymorphisms) are on the average as 1/1000 bases. Thus, the SNPs may affect either the expression or activities of various enzymes and are associated with the differences in drug responses and adverse effects of drugs and toxic chemicals. SNPs are present not only in the mRNA but also in mature miRNA sequences. SNPs in primary (pri)-miRNAs, precursor (pre)-miRNAs, or mature miRNA could modify various biological processes by influencing the processing or target selection of miRNAs (Duan et al., 2007; Iwai and Naraba, 2005). SNPs in pri- or pre-miRNA are relatively rare. Only ∼10% of human pre-miRNAs have documented SNPs and <1% of miRNAs have SNPs in the functional seed sequence region (Saunders et al., 2007). Although seed region variations in miRNA seem to be very rare, they have the potential to influence the expression of hundreds of genes and related pathways. An interesting study regarding the correlation between SNPs in the miRNA sequence and the clinical drug therapy was published by Boni et al. (2010). An SNP (rs7372209) in the pri-miR26a gene and an SNP (rs1834306) in the pri-miR-100 gene were significantly associated with the tumor response or time to progression in 61 metastatic colorectal cancer patients treated with 5-fluorouracil and CPT-11 (Boni et al., 2010). This is the first report to suggest a relationship between the clinical outcome of drug therapy and SNPs in the miRNA-biogenesis machinery, in both primary and precursor miRNAs, but the molecular mechanisms by which these polymorphisms act have not yet been clarified (Shomron, 2010). Compared with the low level of variation in the functional regions of miRNAs, a considerable level of variation at the target sites is conceivable. Many miRNA target-related polymorphisms are reported to be associated with the phenotypes of diseases because a gain-of-function or loss-of-function would result in changes in the expression of target mRNAs (Sethupathy and Collins, 2008). However, actually, there are few examples regarding miRNA-related polymorphisms affecting the drug response, adverse reactions, and toxicological outcomes, such as human dehydrofolate reductase (DHFR) and sulfotransferase isoform 1A1 (SULT1A1) as mentioned later. Recent genome-wide analyses of human SNPs have revealed that many polymorphisms exist in the miRNA binding sites. Approximately 400 SNPs were found at verified target sites or predicted target sites, and about 250 SNPs potentially create novel target sites for miRNAs in humans (Saunders et al., 2007). More recently, roughly 20,0000 miRNA target-related polymorphisms were systematically searched using Patrocles (http://www.patrocles.org/Patrocles.htm) and PolymiRTS (http://compbio.uthsc.edu/miRSNP/). Those in silico-predicted database should be carefully validated by functional studies in the future. Concerning an miRNA target polymorphism in relation to drug-metabolizing enzymes, it was demonstrated that a C829T SNP, a naturally occurring SNP, at the miR-24 recognition site in the 3′-UTR of human DHFR leads to DHFR overexpression and methotrexate resistance (Mishra et al., 2007). Cells with the mutant 3′-UTR had a twofold increase in DHFR mRNA half-life, expressed higher levels of DHFR mRNA and DHFR protein, and were fourfold more resistant to methotrexate as compared with wild-type cells. In a case-controlled study of childhood leukemia patients, those possessing C to T SNP occurred with 14.2% allelic frequency in the Japanese population. The T allele of the SNP resulted in the loss of the miR-24-mediated regulation of DHFR, high DHFR protein levels and methotrexate resistance. This finding may be useful in predicting the clinical efficacy of methotrexate treatment (Mishra et al., 2007; Mishra and Bertino, 2009). Sulfotransferase isoform 1A1 (SULT1A1) is one of the essential enzymes in the metabolism of endo- and exobiotics and dietary and environmental procarcinogen/promutagen activation and/or detoxification. SULT1A1 activity shows high interindividual variability in the expression of the protein (Jones et al., 1993) and a genetic polymorphism was suggested, although not fully accounted for by the variation of SULT1A1 activity. An SNP in the 3′-UTR (972C>T [rs1042157]) is significantly associated with the SULT1A1 mRNA level (p = 0.029) and enzymatic activity (p = 0.012) (Yu et al., 2010). From subsequent functional analyses, it was found that miR-631 directly regulates SULT1A1 expression in an allele-specific manner of the 3′-UTR (SNP of 972 C > T), which provides new insight into the mechanism of SULT1A1 regulation and new information for molecular epidemiology and risk assessment studies of heterocyclic amines such as N-hydroxyarylamines, N-hydroxy-heterocyclic amines, and arylhydroxamic acids. Drug responses or susceptibility to xenobiotic toxicity will be predicted by miRNA expression profiles. Interindividual variability in adverse drug responses and toxicity will be predicted partly by using miRNA-related polymorphisms. This new class of miRNA-related polymorphisms may contribute to the interindividual differences in drug responses and toxicant-induced adverse events. miRNAs IN PLASMA AS POTENTIAL TOXICOLOGICAL BIOMARKERS Circulating miRNA in plasma was first demonstrated as diagnostic biomarkers of lung (Chen et al., 2008), colorectal (Chen et al., 2008), and prostate cancers (Mitchell et al., 2008). The dynamic changes of circulating miRNAs in the plasma resulting from drug exposure was first demonstrated by Wang et al. (2009). In mice, acetaminophen increased miR-122 and miR-192 in liver and plasma in a dose- and exposure-duration manner that paralleled ALT and histopathological changes in the liver. The changes of miRNAs were earlier than those of ALT. This discovery of plasma miRNA opens up the great possibility of using miRNAs as a sensitive, informative, and non-invasive potential biomarker for drug-induced liver injury and toxicological outcomes. Many studies have already been conducted regarding circulating miRNA and the clinical diagnosis and prognosis of cancer, but few papers have been published in relation to toxicological studies. It was reported that increased plasma concentrations of miR-122, miR-133a, and miR-124 corresponded to injuries in liver, muscle, and brain, respectively, although each of these is the abundant and specific miRNA in each organ (Laterza et al., 2009). The miR-122 concentration in plasma increased earlier than the increase of aminotransferase activities in the blood (Zhang et al., 2010). This change was more specific for viral-, alcohol-, and chemical-related liver injury than other organ damage and was a more stable and reliable biomarker (Zhang et al., 2010). Although several challenges remain to be addressed, circulating miRNAs have great potential in toxicological studies, e.g., as a novel, noninvasive method for the extrapolation of the toxicity data from animal to human. CONCLUSIONS This review has described several examples of miRNAs and their relationship to drug-metabolizing enzymes, their interactions with nuclear receptors as well as implications for toxicological studies. Although the field of miRNA-related drug metabolism and toxicology studies is still in its infancy, we are now entering an interesting period in which the contribution of miRNAs in controlling various pharmacological and toxicological outcome will become more clear. In the near future, miRNA profiling may lead to the discovery of novel miRNA biomarkers that might improve the prediction of metabolic activation and detoxification of drugs in vivo in human. As the methodologies for miRNA studies are now becoming more widespread, comprehensive understanding of miRNAs is expected to progress in toxicology. FUNDING Health and Labor Science Research Grant (H23-BIO-G001) from the Ministry of Health, Labor and Welfare of Japan. FIG. 1. Open in new tabDownload slide miRNA-related networks of cytochrome P450 and nuclear receptors. FIG. 1. Open in new tabDownload slide miRNA-related networks of cytochrome P450 and nuclear receptors. We acknowledge Mr. Brent Bell for reviewing the manuscript. References Abdel-Razzak Z , Loyer P , Fautrel A , Gautier J-C , Corcos L , Turlin B , Beaune P , Guillouzo A . Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture , Mol. Pharmacol. , 1993 , vol. 44 (pg. 707 - 715 ) Google Scholar PubMed OpenURL Placeholder Text WorldCat Adams BD , Furneaux H , White BA . The micro-ribonucleic acid (miRNA). miR-206 targets the human estrogen receptor-α (ERα) and represses ERα messenger RNA and protein expression in breast cancer cell lines , Mol. Pharmacol. , 2007 , vol. 21 (pg. 1132 - 1147 ) OpenURL Placeholder Text WorldCat Alexiou P , Maragkakis M , Papadopoulos GL , Reczko M , Hatzigeorgiou AG . 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TI - Toxicological Implications of Modulation of Gene Expression by MicroRNAs
JO - Toxicological Sciences
DO - 10.1093/toxsci/kfr168
DA - 2011-09-01
UR - https://www.deepdyve.com/lp/oxford-university-press/toxicological-implications-of-modulation-of-gene-expression-by-5eH4ybBQsh
SP - 1
EP - 14
VL - 123
IS - 1
DP - DeepDyve
ER -