Drug Metab. Pharmacokinet. 21 (6): 437–457 (2006).

Review Nuclear -Mediated Transcriptional Regulation in Phase I, II, and III Xenobiotic Metabolizing Systems

Kotoko NAKATA1,YoshitomoTANAKA2, Tatsuya NAKANO3, Tatsuhiko ADACHI4, Hiroshi TANAKA2,TsuguchikaKAMINUMA2 and Toshihisa ISHIKAWA4* 1Advance Soft CorporationWIIS, University of Tokyo, Tokyo, Japan 2Tokyo Medical and Dental University, Tokyo, Japan 3National Institute of Health Sciences, Tokyo, Japan 4Tokyo Institute of Technology, Yokohama, Japan

Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk

Summary: Studies of the genetic regulation involved in drug metabolizing enzymes and drug transport- ers are of great interest to understand the molecular mechanisms of drug response and toxic events. Recent reports have revealed that hydrophobic ligands and several nuclear receptors are involved in the induction or down-regulation of various enzymes and transporters involved in Phase I, II, and III xenobiotic metabolizing systems. Nuclear receptors (NRs) form a family of ligand-activated transcription factors (TFs). These modulate the regulation of target by contacting their promoter or enhancer sequences at speciˆc recognition sites. These target genes include metabolizing enzymes such as cytochrome P450s (CYPs), transporters, and NRs. Thus it was now recognized that these NRs play essential role in sensing processing xenobiotic substances including drugs, environmental chemical pollutants and nutritional ingredients. From literature, we picked up target genes of each NR in xenobiotic response systems. Possible cross-talk, by which xenobiotics may exert undesirable eŠects, was listed. For example, the role of NRs was comprehensively drawn up in cholesterol and bile acid homeostasis in human hepatocyte. Summarizing current states of related research, especially for in silico response element search, we tried to elucidate mediated xenobiotic processing loops and direct future research.

Key words: nuclear receptor; ; induction; drug metabolism; ABC transporter, xenobiotics, oxidative stress

process of xenobiotics. In some cases, however, the Introduction phase II system is a critical step in the formation of The metabolism of xenobiotics including drugs is genotoxic electrophiles. Furthurmore, accumulation of widely referred to as comprising phase I and phase II the resulting metabolites in cells can lead to a decrease in systems, where phase I includes the oxidation of the detoxiˆcation activity of the phase II system. There- xenobiotics and phase II deals with the conjugation of fore, a membrane transport system must perform the phase I products. The oxidative metabolism process in task of eliminating phase II metabolites from cells. In the phase I system is mediated by cytochrome P-450 1992, Ishikawa proposed a new concept for the ``phase (CYP) or ‰avin mixed-function oxidase. Some activated III'' detoxiˆcation system by emphasizing the biological xenobiotics can interact with DNA andWor proteins in importance of ATP-dependent export pumps (Fig. 1).1) cells to cause toxic eŠects. In the phase II system, on the Since that time, more than 40 diŠerent human ATP- other hand, activated hydrophobic xenobiotics are binding cassette (ABC) transporter genes have been converted into hydrophilic forms via conjugation discovered, and some of them, e.g., ABCB1, ABCB11, reactions with glutathione, sulfate, or glucuronide. This ABCC1, ABCC2, and ABCG2, have been demonstrat- phase II metabolism is regarded as the detoxiˆcation ed to be critically involved in the transport of xenobiot-

Received; July 30, 2006, Accepted; October 10, 2006 *To whom correspondence should be addressed: Toshihisa ISHIKAWA,Ph.D.,Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-60 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan. Tel. ＋81-45-924- 5848, Fax. ＋81-45-924-5838, E-mail: tishikaw＠bio.titech.ac.jp

437 438 Kotoko NAKATA, et al.

and disposition. Nuclear Receptors and their Ligands The nuclear receptors (NRs) function as ligand- activated transcription factors (TFs) and regulate the expression of genes whose products are essential for embryonic development, maintenance of diŠerentiated cellular phenotypes, metabolic disorders including obesity, type 2 diabetes, hyperlipidemia, hypertension, and atherosclerosis, and cell death.6,7) The uniˆed nomenclature system for the nuclear receptor super- family was adopted in 1999.8) On the basis of their sequences, 48 members of the NR family were reported,9) which included not only the classical endocrine receptors that mediate the actions of Fig. 1. Schematic illustration of phase I, II, and III drug metaboliz- steroid hormones, thyroid hormones, and the fat- ing systems and the role of nuclear receptors in the induction of 10) enzymes and transporters in those systems. The phase I system soluble vitamins A and D, but also a large number of 11) involves cytochrome P-450 (CYP) or ‰avin mixed-function oxidase orphan nuclear receptors. As Otte et al. recently that catalyzes oxidation reactions of xenobiotics (X). The phase II identiˆed the FXR b sensing lanosterol,12) 49 members system deals with the conjugation of phase I products (Y) to form a wereincludedinthemammalianNRfamily.Itisa variety of conjugate metabolites (Z). Transporters in the phase III functional receptor in mice, rats, rabbits and dogs, but system eliminate phase II metabolites from cells. Hydrophobic ligands (xenobiotics andWor metabolites) and nuclear receptors are critically constitutes a pseudogene in human and primates. involved in the induction or down-regulation of various enzymes and The classical endocrine receptors that mediate the transporters (target genes) involved in Phase I, II, and III drug actions of steroid hormones include the glucocorticoid metabolizing systems. (GR), mineralocorticoid (MR), estrogen (ER), androgen (AR), and progesterone (PR) receptors. These steroid ics and metabolites. Besides those ABC transporters, receptors bind to DNA as homodimers, and their currently accumulating evidence strongly suggests that ligands are synthesized from endogenous endocrine other ABC transporters, such as ABCA1, ABCG1, sources that are regulated by negative-feedback control ABCG5, and ABCG8, are also playing signiˆcant roles of the hypothalamic axis.13) Although ligands, target in the eŒux of steroids and oxysterols, under regulation genes, and physiological functions of the orphan NRs by nuclear receptors and their ligands. were initially unknown, exciting progress has been made Hitherto, it has been well documented that many over the last several years in elucidating their role in inducers of drug metabolizing enzymes in Phase I and development, homeostasis, and disease. Those receptors Phase II share common mechanisms of transcriptional that are shown to bind a physiological ligand become activation and share a similar battery of genes that are adopted orphan nuclear receptors and function as a coordinately regulated. Along with the induction of heterodimer with (RXR). They phase I andWor phase II enzymes, it has been shown that include receptors for fatty acids (peroxisome prolifer- pretreatments with several types of inducers alter the ator-activated receptors: PPARs), oxysterols (liver X expression of phase III transporter genes (Table 1), receptor: LXRs), bile acids (farnesol X receptor: FXR), suggesting that common regulatory mechanisms may and xenobiotics (: PXR). Dysfunc- exist for those genes. Indeed, the phase III transporter tion of nuclear receptor signaling leads to proliferative, MRP1 (ABCC1) and g-glutamylcysteinyl synthetase reproductive and metabolic diseases such as cancer, ( g-GCS) were ˆrst demonstrated to be coordinately infertility, obesity, and diabetes. Thus, to maintain a induced by t-butylhydroquinone ( t-BHQ), cisplatin, normal physiological state, the spatial and temporal and heavy metals.2–4) To know whether inducers of activity of NRs must be tightly controlled by tissue- phase I and phase II enzymes coordinately regulate the speciˆc expression of the receptors. phase III transporter genes requires further studies, and The NR molecules are composed of four such information would add to our knowledge of the modules: the modulator domain carrying a ligand- metabolism and elimination of xenobiotics. In this independent transcription activation function (AF-1); regard, Kaminuma described the chemical computing the DNA-binding domain (DBD); the hinge region; and and bioinformatics viewpoint on nuclear receptors in the ligand-binding domain (LBD) (Fig. 2). The DBD proposing a project entitled ``Nuclear Receptors and allows the nuclear hormone receptors to bind response Syndrome X'' in 2003.5) We here present an overview on elements within the promoters of target genes, as the role of nuclear receptors in xenobiotic metabolism monomeric proteins or as homo or heterodimers. Nuclear Receptors and Regulation of Drug Metabolism Genes 439

Table 1. Nuclear receptor-ligand interactions and their eŠect on the expression of drug metabolizing enzymes (Phase I & II) and ABC transport- ers (Phase III).

Target Ligand NR Response element Phase I Phase II Phase III

Xenobiotics AhR XRE CYP1A1 (＋)UGT1A1(＋)ABCG2(＋) CYP1A2 (＋)UGT1A6(＋) CYP1B1 (＋)

Xenobiotics CAR DR-3, DR-4, DR-5 CYP2A6 (＋)UGT1A1(＋) ABCC2 (＋) Phenobarbital SR-6, ER-6 CYP2B1 (＋) ABCC3 (＋) CYP2B6 (＋) ABCC4 (＋) CYP2C9 (＋) CYP2C19 (＋)

Xenobiotics SXRWPXR DR-3, DR-4, DR-5 CYP1A2 (＋) SULT2A1 (＋)ABCA1(＋) Steroids ER-6, ER-8 CYP2B6 (＋)UGT1A1(＋) ABCB1 (＋) CYP2C9 (＋)UGT1A3(＋) ABCB11 (＋) CYP2C19 (＋)UGT1A4(＋) ABCC1 (＋) CYP3A4 ABCC2 (＋) CYP3A7 ABCC3 (＋) CYP7A1 (－)ABCG2(＋) CYP3A (＋)

Bile acids FXR IR-1 CYP7A1 (－)UGT2B4(＋) ABCB4 (＋) DR-1 CYP8B1 (－) SULT2A1 (＋) ABCB11 (＋) ABCC2 (＋)

Oxysterols LXRa, b DR-4 CYP2B6 (－)ABCA1(＋) CYP3A4 (－)ABCG1(＋) ABCG4 (＋) ABCG5 (＋) ABCG8 (＋)

Fatty acids PPARa DR-1 CYP4A1 (＋)UGT1A9(＋)ABCA1(＋) Fibrates CYP4A3 (＋)UGT2B4(＋) ABCC2 (＋) CYP7A ABCD2 (＋) ABCD3 (＋)

Fatty acids PPARd CYP4A (＋)UGT1A(＋)ABCA1(＋) Carboprostacyclin

Eicosanoids PPARg CYP4AB (＋)UGT1A9(＋)ABCA1(＋) Thiazolidinediones ABCG2 (＋)

Retinoic acids RARa, b, g CYP2B6 (＋) ABCB1 (＋) ABCG4 (＋)

1,25(OH)2- VDR DR-3 CYP2B6 (＋) SULT2A1 (＋) ABCC2 (＋)?

vitamin D3 ER-6 CYP2C9 (＋) IR-0 CYP3A4 (＋)

Gluco- GR GRE CYP2C9 (＋) Corticoid CYP2B6 (＋) CYP3A4 (＋)

ROS Nrf2 ARE g-GCS (＋) ABCC1 (＋)? Electrophiles GST (＋) ABCC2 (＋) NQO1 (＋) ABCC3 (＋) UGT (＋)ABCG2(＋)? HO-1 (＋)

ROS, reactive oxygen species; (＋), up-regulation; (－), down-regulation.

Ligand-dependent activation function 2 (AF-2) is the core histones H2A, H2B, H3, and H4.14) Non- localized at the carboxy-terminal end of the LBD. In acetylated histones form highly condensed heter- eukaryotes, DNA is coiled around histones, which are ochromatin that cannot be transcribed, because the constructed by the linker histone H1 and an octamer of RNA polymerase cannot bind to the promoters. The 440 Kotoko NAKATA, et al.

Fig. 3. Sensor-processor model in the xenobiotic response system. An nuclear receptor (NR) acts as a ``sensor'' that recognizes and binds a speciˆc ligand. The subsequent binding of NR with histone leads to Fig. 2. Schematic illustration of the nuclear receptor with diŠerent the recruitment of histone acetyl transferase (HAT). Acetylation of modules: the ligand-independent transcription activation domain histone catalyzed by HAT results in the formation of less-condensed (AF-1 and AF-2), the DNA-binding domain (DBD), the hinge euchromatin. The ligand-bound NR associates with transcriptional domain, and the ligand-binding domain (LBD). The receptors are coregulator proteins, and thereby the target genes are transcribed by (ER), Aryl hydrocarbon receptor (AhR), Pregnane RNA polymerase II (RNApol II). Drug enzymes andWor transporters, X receptor (PXR), (VDR), Constitutive thus de novo synthesized, act as ``processors'' for xenobiotic androstane receptor (CAR), (FXR), Liver X metabolism and disposition. receptor (LXR), Peroxisome proliferators-activated receptors a, g, d The symbol `` '' means a nucleosome. (PPARa, g, d ) and (RXRa). AWB: ligand- independent transcription activation function 1 (AF-1); C: DNA- binding domain (DBD); D: hinge domain; E: C-terminal hormone- can interact with and be activated by intracellular binding domain (HBD); F: C-terminal extension (F); EWF: ligand- xenobiotics, they are often designated as xeno- dependent activation function 2 (AF-2) sensors.18,19) As FXR, PXR, and VDR are bile acid receptors to regulate bile acid metabolism, these initial binding between NR and histon recruits Histone receptors are sometimes called as lipid sensors. Acetyl Transferase (HAT). Then, acetylated histones However, these receptors also bind to xenobiotics and form less condensed euchromatin. Ligand-binding NRs act as xenobiotic sensors. In mammals, three kinds of induce association with various kinds of coregulators, transcription factor superfamilies are identiˆed as and then the target genes are transcribed by RNA poly- xenobiotic sensors: basic-helix-loop-helixWPer-ARNT- merase II (RNApol II).15,16) Figure 3 schematically illus- Sim (bHLH-PAS) proteins, NRs and basic leucine trates the sensor-processor model of the xenobiotic zipper (bZIP) proteins. Those sensor proteins bind ˆrst response system. to the ligand and then the DNA response element (RE). Recently, a chromatin immunoprecipitation (ChIP) The expressed genes are translated into processor assay has been developed as a well-established and proteins, which are summarized in Fig. 3 with their reliable method for analyzing the DNA binding site of a co-regulators. protein. Coupled with whole-genome DNA microar- AhR: The aryl hydrocarbon receptor (AhR), AhR rays, ChIP-Microarray (also call ChIP-chip) experi- repressor (AhRR), and AhR nuclear translocator ments are able to identify the precise position of protein (ARNT) are members of the bHLH-PAS transcription binding sites on the genome and can be used to measure factor (TF) superfamily. AhR mediates the pleiotropic relative transcript levels. ChIP-chip or genome-wide eŠects of various environmental contaminants, such as location analysis has become the premier tool for high- 2,3,7,-tetrachlorodibenzo-p-dioxin (TCDD), including throughput elucidation of gene-regulatory interac- teratogenesis, tumor promotion, thymic atrophy, tions.17) epithelial hyperplasia, hepatotoxicity, and induction of drug-metabolizing enzymes.20–22) Subsequent heter- Xenobiotic Response Systems odimerization of AhR with the ARNT, and binding of Xenobiotic chemicals, such as drugs and environmen- the complex to xenobiotic response elements (XRE) of tal chemicals, are absorbed by the intestine and target genes, induce the expression of the drug delivered to the target sites (NRs, membrane receptors, metabolizing enzymes cytochrome P450-1A (CYP1A), enzymes, transporters). Because AhR, PXR and CAR CYP1B, UDP-Glucronosyltransferase-1A (UGT1A), Nuclear Receptors and Regulation of Drug Metabolism Genes 441

Glutation S-transferase (GST), and a factor designated (BCRPWABCG2).28–30) In contrast, docetaxel (Taxotere) AhR repressor (AhRR) genes. AhRR inhibits AhR displays superior pharmacokinetic properties, and function by competing with AhR to dimerize with Ecteinascidin-743 (ET-743) suppresses MDR1 transcrip- ARNT and bind to the XRE sequence. Consequently, tion by acting as an inhibitor of SXR.31) Thus PXR is a AhR and AhRR form a regulatory circuit in the broad-speciˆcity xenobiotic sensor with a central role in xenobiotic signal transduction pathway, and provide a regulating hepatic drug metabolism to protect the body mechanism for regulating AhR function as a tissue- from harmful chemicals.32) speciˆc sensor of environmental pollutants.21) In Kliewer33) reported that PXR regulates not only addition, via the increased cAMP level and protein CYP3A, but also an entire set of genes that are Kinase A (PKA) activity, TCDD activates the binding important in xenobiotic metabolism, including those of CRE-binding protein (CREB) to CRE and aŠected encoding proteins in phase I metabolism (oxidation), the CCATWenhancer-binding protein b (CWEBPb )gene phase II metabolism (conjugation), and phase III trans- transcription.23) port (elimination of metabolites).1) All of these gene ER: Estrogen receptors (ERs), ERa (NR3A1) and products are involved in the solubilization or active ER b (NR3A2), are members of the steroid hormone excretion of drugs and other xenobiotics including St. receptor superfamily, and ligand-dependent transcrip- John's wort, gugulipid and hops. Activation of PXR tion factors. ERs generally bind as homodimers to protects against the hepatotoxic eŠects of high concen- hormone REs that consist of palindromic arrangements. trations of bile acids administered in the diet.27,34,35) ERs play a multitude of essential roles not only in Sonoda et al. reported that the PXR signaling pathway development, homeostasis, reproduction, and immune protects the body from toxic dietary cholesterol metabo- functions, but also in various types of cancer (breast, lites and that a PXR ligand may ameliorate cholestatic ovarian, colorectal, prostate, endometrial), osteoporo- liver disease and the associated acute and renal sis, neurodegenerative diseases, cardiovascular disease, failure.36) and obesity.24) The ChIP assay was used to identify 89 While Blumberg reported that certain highly chlori- targetgenesofERa, including ABC transporter nated polychlorinated biphenyls (PCBs) are potent ABCA3, (PGR), cytochrome c, activators of rodent PXR, they antagonize its human solute carrier transporter SLC38A1, and prostaglandin ortholog SXR, inhibiting target gene induction. It Esynthase(PTGES).25) means that exposure to PCBs may blunt the human PXR: The pregnane X receptor (PXRWNR1I2) xenobiotic response, inhibiting the detoxiˆcation of responds to a diverse array of pharmaceutical agents, steroids, bioactive dietary compounds, and xenobitics environmental contaminants, steroids, and toxic bile normally mediated by SXR.37) acids. It binds to xenobiotic response elements as a CAR: The constitutive androstane receptor (CARW heterodimer with the 9-cis retinoic acid receptor (RXR). NR1I3) was originally characterized as a receptor that The steroid xenobiotic receptor (SXR) is human activates a retinoic acid response element (RARE) in the ortholog of PXR. Thus, PXR regulates the variation in absence of a ligand.38) As a heterodimmer with RXR, expression of a gene. Especially, PXR is a key regulator CAR mediates the phenobarbital induction of of CYP3A expression in mammalian liver and small UGT1A1, CYP2B6, CYP3A4, and CYP2C9.35–38) intestine. The CYP3A enzyme is responsible for Phenobarbital and 5b-pregnane are CAR activators and metabolizing and clearing over 50z of clinically clotrimazole, androstenol, and progesterone are CAR prescribed drugs.26) deactivators. CAR is a xenobiotic-sensing receptor that In addition to being a xenobiotic sensor, PXR is is capable of recognizing structurally diverse com- activated by the toxic bile acid lithocholic acid (LCA) pounds.39) and its 3-ketometabolite. Furthermore, PXR regulates VDR: The vitamin D receptor (VDRWNR1I1) is a the expression of genes involved in the biosynthesis, member of the superfamily of steroid hormone transport, and metabolism of bile acids including receptors. It regulates calcium homeostasis, immunity, cholesterol 7a-hydroxylase (Cyp7a1) and the Na＋- cellular diŠerentiation, and other physiological proc- independent organic anion transporting polypeptide 2 esses. The vitamin D3 function is mediated through (Oatp2, slc21a5).27) PXR also regulates drug eŒux by VDR, which forms a heterodimer with RXR after ligand activating expression of the Multidrug resistance 1 binding. Although there is a wide promiscuity of this (MDR1) gene, which encodes the protein P-glycoprotein receptor, ligand-activated VDR has been shown to (MDR1WABCB1).Inhumans,PXRalsomediates induce the expression of CYP2B6, CYP2C9 and CYP3A7, CYP2B6, as well as the bile salt export pump CYP3A4.40–42) Drocourt et al.40) reported that VDR, (BSEP, ABCB11), multidrug resistance associated PXR, and CAR control the basal and inducible protein 1 (MRP1WABCC1), 2 (MRP2WABCC2), 3 expression of these CYP genes through competitive (MRP3WABCC3), and breast cancer resistance protein interaction with the same battery of response elements. 442 Kotoko NAKATA, et al.

Recently, VDR was found to respond to bile acids as cerning which PPARg may be a determinant of cell fate well as do FXR and PXR.42,43) and is likely a target of the WntWb-catenin signaling PPAR: The peroxisome proliferator-activated pathway in colon cancer cells.52) It has recently been receptors a, g, d (PPARa, g, dWNR1C1, 2, 3) are a reported that PPARg regulates expression of the ABC family of fatty acid-activated TFs and dietary lipid transporter ABCG2 and thereby confers cytoprotection sensors, which control lipid homeostasis and cellular to human dendritic cells.53) diŠerentiation. They bind to DR1 hormone-response Due in part to the lack of selective ligands, the ther- elements (HREs) as heterodimers with RXR, where apeutic potential of the PPARd was unknown until DR1 is a direct repeat with 1 bp spacing.44) PPARa is recently. The expression of PPARd is increased during highly expressed in heart, liver, kidney, intestine and the diŠerentiation of human macrophages in vitro.A brown fat, tissues that demonstrate high rates of fatty highly selective agonist of PPARd promotes lipid acid b-oxidation. PPARg1 transcripts are abundantly accumulation in primary human macrophages and in expressed in the spleen, intestine, and white adipose macrophages derived from the human monocytic cell tissue and PPARg2 transcripts are preferentially ex- line THP-1. PPARd is a powerful promoter of pressed in white and brown fat. PPARd also known macrophage lipid accumulation.54) PPARd increases as PPAR b, Nuclear C1 (NUC1), and the fatty acid- cholesterol eŒux from cells, in part, through an increase activated receptor (FAAR) are more widely expressed in in the expression of cholesterol transporter ABCA1.55) adult tissue, especially in the brain, kidney, small PPARd agonists increase glucose metabolism and intestine and Sertoli cells in the testis. promote gene regulatory responses in cultured human PPARa was initially found to respond to hypolipi- skeletal muscle. Recently, the association of PPARd demic drugs, such as ˆbrates. Subsequently, however, it with atherosclerosis, obesity, diabetes, and other meta- was discovered that fatty acids serve as their natural bolic diseases was manifested.56,57) PPARd was identi- ligands. PPARa induces the expression of the fatty acid ˆed as a target of adenomatous polyposis coli (APC) metabolizing enzymes such as several isoforms of the through the analysis of global gene expression proˆles in CYP4A gene subfamily.45) In mice, ABC transporters colorectal cancer (CRC) cells.58) They suggested that bsep (Abcb11) and mdr2 (Abcb4), SLC transporters NSAIDs (non-steroidal anti-in‰ammatory drugs) ntcp and oatp1,46) and phase II metabolism enzymes inhibit tumorigenesis through inhibition of PPARd, UGT2B447) and UGT1A947) are also regulated by which is normally regulated by adenomatous polyposis PPARa. In human macrophages, a PPARa activator coli (APC). Although the functional consequence of induces the expression of the ABC transporter ABCA1 PPARd action in colon carcinogenesis still needs to be gene through a transcriptional cascade mediated by the determined, the aberrant expression of PPARd in nuclear receptor LXRa. Subsequently, ABCA1 controls colorectal tumors was reported.59) apoAI-mediated cholesterol eŒux from macrophages.48) FXR: The farnesoid X receptor (FXRaWNR1H4) is PPARa mediates the hypolipidemic action of ˆbrates; a member of the orphan receptors, and forms a heter- PPARa, b and PPAR-inducible CYP4B1 were detected odimer with RXR. FXR is a global regulator of bile in rabbit corneal epithelial cells.49) acids, including chenodeoxycholic acid, cholic acid, and PPARg is not only the key regulator of adipogenesis, their respective conjugated metabolites.60) In the but also plays an important role in cellular diŠerentia- enterohepatic system, FXR acts as a bile acid sensor that tion, insulin sensitivity, atherosclerosis, and cancer.50) regulates bile acid synthesis and recirculation for the Ligand molecules for PPARg include fatty acids and protection of the body from elevated bile acid concen- other arachidonic acid metabolites, antidiabetic drugs tration. Activation of FXR by bile acids results in (e.g. thiazolidinediones), and triterpenoids. PPARg induction of the phospholipid pump (MDR3WABCB4), activator also induces the expression of the gene encod- bile salt export pump (BSEPWABCB11), organic anion ing ABCA1 and coordinates cholesterol removal in transporting polypeptide 8 (OATP8, SLCO1B3), and macrophages through an indirect mechanism involving small heterodimer partner (SHP, NR0B2) genes to the LXR pathway.6,48) The phase II enzyme gene maintain hepatic extraction of xenobiotics and peptides UGT1A9 was identiˆed as a PPARg target gene.49) under conditions of increased intracellular bile PPARg is a receptor for the antidiabetic glitazones. acids.61,62) FXR negatively regulate the expression of Blumberg et al. reported that an environmental CYP7A and CYP8B, which are rate-limiting enzymes contaminant tributyltin chloride (TBT) binds to and for the production of bile acids (BAs), and Na＋-depen- activates both RXR and PPARg with high a‹nity to dent taurocholate cotransporting polypeptide (NTCP, induce the expression of RXRWPPARg target genes SLC10A1) genes.63) The down-regulation of CYP7A, involved in adipogenesis in vivo.50) The induction of NTCP, and SHP is caused by the up-regulation of SHP adipogenesis is a novel and unexpected endocrine eŠect and the heterodimeric complex of SHP and LRH-1.64) of TBT.51) Other possibilities were also reported con- Holt et al. described another pathway and negative Nuclear Receptors and Regulation of Drug Metabolism Genes 443 regulation of CYP7A1 gene expression.65) FXR HNF4: The hepatocyte nuclear factor 4 (HNF4aW regulates the expression of ˆbroblast growth factor-19 NR2A1) is a transcription factor of the nuclear (FGF-19), a secreted growth factor that signals through family that is expressed in the hepatic the FGFR4 cell-surface receptor tyrosine kinase. diverticulum at the onset of liver development. The liver Subsequently, FGF-19 strongly suppresses the expres- represents the major site for P450-mediated oxidative sion of CYP7A1 through a c-Jun N-terminal kinase metabolism, although particular P450 forms are (JNK)-dependent pathway. In the liver, phosphorlipid expressed in extrahepatic tissues such as intestine, lung transfer protein (PLTP), apolipoprotein E (Apo E), and and kidneys. Although an endogenous ligand for apolipoprotein CII (ApoC-II) are induced by activated HNF4a has yet to be identiˆed, fatty acyl-coenzyme A FXR.66) In the ileal enterocytes, bile acid and FXR thioesters bind to the binding domain.78) HNF4a binds complex induce the expression of the cytosolic intestinal as a homodimer to the response elements containing bile acid binding protein (I-BABP) and the ileal bile acid DR1 of the hexamer AGGTCA.79) transporter I-BAT.67) HNF4a is an important regulator coordinating the Otte et al.12) identiˆed FXR b,bydataminingof NR-mediated response to xenobiotics.80,81) By using an human and mouse genomic sequences. They reported adenoviral vector for e‹cient expression of HNF4a that it is a functional receptor in mice, rats, rabbits, and antisence RNA, Jover et al.80) showed that the dogs but constitutes a pseudogene in humans and expression of CYP3A4, CYP3A5, and CYP2A6 was a primates. They also identiˆed lanosterol as a candidate dose-dependent down-regulation on the blockage of endogenous ligand that induces coactivator recruitment HNF4 translation, and that a moderate inhibition of and transcriptional activation by mouse FXR b. CYP2B6, CYP2C9, and CYP2D6 expression was LXR: The liver X receptors LXRa (NR1H3) and observed. Kamiya et al.81) showed that HNF4a is the key LXR b (NR1H2), which form heterodimers with RXR, transcription factor regulating responses to xenobiotics are bound and activated by naturally occurring oxys- through activation of the PXR gene during fetal liver terols, other small lipophilic agents, certain unsaturated development. Jung et al.82) showed that OATP-C fatty acid, and geranylgeranyl pyrophosphate.64,68–71) (SLCO1B1) is activated by hepatocyte nuclear factor LXRs are expressed not only in the liver, but also (HNF) 1a, which is dependent on HNF4a.WithChIP abundantly in other tissues associated with lipid meta- experiments, Odom et al.83) identiˆed more than 222 bolism, whereas LXR b is ubiquitously expressed.64) target genes of HNF4a including CREB-like 2 LXRs act as cholesterol sensors to regulate the (CREBL2), insulin receptor (INSR), human OAT4 transcription of gene products that control intracellular (SLC22A11), and liver canalicular multispeciˆc organic cholesterol homeostasis through biosynthesis, anion transporter MRP2WcMOAT (ABCC2). catabolism, and transport. When cholesterol levels Nrf2-Keap1: Nuclear factor erythroid 2 P45-related increase in rodent hepatocytes, LXRa is activated by factor (Nrf2) is a basic (bZIP) redox- oxysterols and stimulates the conversion of cholesterol sensitive transcription factor that deˆnes one of to bile acids by inducing CYP7A1 transcription.72) the physiologically important stress response mechan- However, activation of LXRa has the opposite eŠect in isms.84) Under basal conditions, Nrf2 binds to Kelch-like human and rodent liver. In humans, repression of ECH-associated protein1 (Keap1) in the cytoplasm. CYP7A1 expression is mediated, at least in part, Electrophiles and oxidative stress disrupt the Nrf2- through induction of SHP, which is regulated directly Keap1 complex, allowing Nrf2 to translocate to the by LXRa.73) LXRa regulates a number of genes in- nucleus. Then Nrf2 binds to antioxidant response volved in cholesterol andWor lipid homeostasis including element (ARE) with heterodimeric combinations with ABC transporters ABCA1, ABCG1, ABCG4, ABCG5 other basic leucine zipper proteins, such as small Mafs, and ABCG8, cholesterol ester transport protein and regulates gene expression of detoxifying enzymes, (CETP), lipoprotein lipase (LPL) fatty acid synthase, such as glutathione S-transferase (GST), NAD(P)H:qui- and the sterol-regulating element binding protein 1 none oxidoreductase-1 (NQO1), UGT, g-glutamyl- (SREBP-1).74–76) cysteine synthetase ( g-GCS), and heme oxygenase 1 LXRa regulates the LPL gene in the liver and (HO-1).85,86) Morimitsu et al.87) found Japanese horse macrophages. LPL is a key enzyme for lipoprotein radish, wasabi, as the richest inducer source and identi- metabolism and is responsible for hydrolysis of ˆed 6-methylsulˆnylhexyl isothiocyanate (6-HITC), an triglycerides in circulating lipoproteins, releasing free analog of sulforaphane (4-methylsulˆnylbutyl isothioc- fatty acids to peripheral tissues.77) LXRs act as yanate) isolated from broccoli, as the major GST cholesterolsensorsthatrespondtoelevatedsterol inducer in wasabi. concentrations and transactivate a cadre of genes that Ishikawa and Kuo previously demonstrated that govern transport, catabolism, and elimination of expression of MRP1 (ABCC1) and g-GCS can be cholesterol. coordinately induced by many cytotoxic agents, includ- 444 Kotoko NAKATA, et al.

helix-loop-helix leucine zipper family (bHLH-Zip). SREBPs are encoded by two genes SREBP-1 and SREBP-2. SREBP-1 has two isoforms, SREBP-1a and SREBP-1c. SREBP-1c activates genes encoding en- zymes involved in fatty acid synthesis and drives the formation of triglycerides and phospholipids. SREBP-2 stimulates the transcription of genes encoding enzymes involved in cholesterol synthesis. Both SREBP-1c and SREBP-2 regulate the three enzymes, malic enzyme (ME), glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (PGDH).102) By using the ChIP analysis, Bennett and Osborne103) report- ed that SREBP regulates the low density lipoprotein (LDL) receptor gene with the coregulatory factor Sp1 and the hydroxymethyl glutaryl CoA reductase (HMG- CoA) gene with two coregulatory factors, i.e., CAAT box binding factorWnuclear factor Y (CBFWNF-Y; Fig. 4. Oxidative stress-induced transcriptional activation of g-GCS herein referred to as NF-Y) and cAMP response element gene. Activation of g-GCS involves transcription factor Nrf2, which is complexed with Keap1 and bound by cytoplasmic actin. Oxidative binding protein (CREB)Wactivating transcription factor stress induces dissociation of Keap1 from Nrf2, either by phosphory- (ATF). Together with CREB, SREBP-1a regulates lation of Nrf2 or by conformational changes in Keap1. The released lanosterol 14a-demethylase (CYP51).104) Nrf2 translocates into the nucleus, heterodimerizes with MafK, and CWEBP: The CCAATWenhancer-binding protein activates the expression of g-GCS. Alternatively, oxidative stress may (CWEBP) is a member of the basic leucine zipper family activate Keap1, which suppresses the ubiquitination and degradation of Nrf2. These mechanisms result in nuclear accumulation of Nrf2 (bZIP) and a liver-enriched transcription factor. Six and subsequent transcriptional activation. isotypes of CWEBP are identiˆed, namely a, b, g, d, e, and z.CWEBP has been predicted to play roles in cellular proliferation and diŠerentiation, metabolism, ing antitumor agents, heavy metals, carcinogens, and and in‰ammation particularly in hepatocytes, adipo- prooxidants.2–4,88–91) Furthermore, enhanced expression cytes, and haematopoietic cells.105) C WEBP regulates the of g-GCSh mRNA was found in colorectal cancers.92,93) expression of human and mouse NTCPWNtcp, but not All these inducers, at the concentrations used, exert that of rat.106) By the use of ChIP analysis, Salma various extents of oxidative stresses. These observations et al.107) revealed that CWEBP protein induced adipogen- strongly suggested that the GSHWg-GCS system is a ic genes in diŠerentiating cells. molecular sensor of oxidative stress conditions. While CREB, CREM, ATF-1: Transcriptional factors elevated expression of the heavy subunit of g-GCS binding to cAMP-responsive elements (CREs) in the ( g-GCSh) catalyzes the enhanced expression of GSH, promoters of various genes belong to the basic domain- importantly, we observed that increased GSH levels leucine zipper (bZIP) superfamily and comprise three exerts a feedback eŠect and down-regulate the steady- genes in mammals, CRE binding protein (CREB), CRE state level of g-GCSh mRNA4) in addition to suppress- modulator (CREM), and ATF-1. CREB is a key tran- ing g-GCSh enzymatic activities as reported previous- scription factor that can be activated by hormone ly.94,95) This feedback mechanism underscores the stimulation and stimulates the expression of numerous importance of g-GCShasamajorredoxregulator. genes in response to growth factors, hormones, neu- Transcriptional upregulation of g-GCSh expression is rotransmitters, ion ‰uxes, and stress signals. CREB mediated by ARE located at -3802 bp,96,97) although functions either by itself or with CREM or ATF-1, other investigators also reported the involvement of an homo- and hetero-dimerized through bZIP domains. AP-1 binding site98–100) at the 5? side of the g-GCSh gene. The binding site for them in many cellular CRE contains The ARE contains a consensus sequence 5?-TGAGW the palindrome sequence TGACGTCA. Phosphoryla- CNNNGC, which is a target of the transcription factor tion of CREB at Ser-133 leads to the recruitment of Nrf2 (Fig. 4). That Nrf2 is involved in g-GCSh expres- CREB binding protein (CBP) or its paralog p300 and sion in vivo is supported by the northern blot analyses subsequent transcriptional activation. CREB activates of liver g-GCSh mRNA, which shows a 58z reduction PGC1A gene transcription in hepatocytes,108) and in Nrf2(－W－) cells as compared with the wild-type together with SREBP transactivates CYP51 gene.104) control cells.101) The chromatin immunoprecipitation of CREB-associ- SREBP: The sterol regulatory element binding ated DNA has been used to discover a number of proteins (SREBPs) are transcription factors of the basic targets, including transcription factors (e.g., PPARa Nuclear Receptors and Regulation of Drug Metabolism Genes 445

Fig. 5. Schematic diagram of overall xenobiotic responsive systems. iNOS: inducible nitric oxide synthase, GST: glutathione S-transferase NQO: NAD(P)H:quinone oxidoreductase and MKL1) and signal transduction (e.g., MAPK1, and glucose-6-phosphatase,118) LXR for the ABCA1 BCR).109) gene119) and ERRs for the ERRs gene and medium-chain CBP: CREB-binding protein (CBP) and p300 are acyl-coenzyme A dehydrogenase (MCAD) gene.120,121) often referred to as a single entity, as the two proteins As for non-NR PGC-1 partners, there are muscle-selec- are considered structural and functional homologs. tive transcription factor (myocyte enhancer factor-2: P300WCBP is a transcriptional coactivator, which is MEF-2) for the GLUT4 gene,122) forkhead box O1 considered a pivotal molecule involved in the communi- (FOXO1) for insulin-regulated gluconeogenesis,123) cation between transcription factors and the basal SREBP1 for the lipogenic gene,118) and Sry-related transcription machinery. P300WCBP participates in the HMG box-9 (Sox9) for the chondrogenic gene.124,125) activities of many transcription factors, including Cross talk in Metabolic Pathways steroid genic factor-1WAd-4 binding protein (SF-1W Ad4BP), CWEBPb, GATA-4, and CREB, for regulation Because they share common ancestors, members of of Steroidogenic acute regulatory protein (StAR) gene, the NR superfamily have conserved the capability of which encodes a key protein regulating the steroid interfering functionally with other signaling pathways. hormone synthesis.110) The transcriptional coactivator For instance, PXR and CAR, which are speciˆc recep- p300WCBP has histone acetyltransferase (HAT) activity tors controlling the coordinated expression of xenobiot- and contributes to the gene expression in concert with ic metabolizing and transporter systems (XMTS) in the cellular p300WCBP associated factor (PCAF).111) response to xenobiotics, share common ancestors with PGC-1: PPARg coactivator-1 (PGC-1) is a tran- other NRs including vitamin D, thyroid, and steroid scriptional coactivator. The PGC-1 coactivator family receptors, which control endogenous metabolism. consists of PGC-1a,PGC-1b (also termed PGC-1 Similarly the AhR can interact with other receptors or related estrogen receptor coactivator: PERC), and interfere with other signaling pathways.19) Cross-talk PGC-1 related coactivator (PRC). PGC-1 cooperates between NR controlling XMTS expression and other with PPARa in transcriptional controlling the transcrip- NRs represents another means by which xenobiotics tion of nuclear genes encoding mitochondrial fatty acid may exert undesirable eŠects, such as adverse eŠects of oxidation (FAO) enzymes,112) and likewise with PPARd drugs. An overall ‰owchart of xenobiotic responsive in fatty acid oxidation enzymes.113) systems is shown in Fig. 5. Possible cross-talk or The targets of PGC-1 as transcriptional coactivators functional interference between two diŠerent NRs (TFs) are (TR) and PPARg for the that might aŠect xenobiotic metabolism and toxicity are uncoupling protein 1 (UCP-1) gene,114) ER, MR, and outlined below. GR for each NR gene,115) PPARg and HNF4a and FXR 1) Sharing ligands for the FXR gene,116) PXR117) for its transcription activa-  Phenobarbital activates both PXR and CAR.126,127) tion, HNF4 for the genes encoding gluconeogenesis  Lithocolic acid can bind to and activate VDR and enzymes, such as phosphoenol-pyruvate carboxykinase PXR.19) 446 Kotoko NAKATA, et al.

 Progesterone and Dexamethasone bind to AR, ER, cholesterol metabolite oxysterol, regulate the transcrip- GR, MR, and PR.19) tion of the following gene products that control intracel-  Estradiol can bind to AR, ER, and GR.19) lular cholesterol homeostasis through catabolism and 2) Sharing response elements transport: SREBP, SHP, ABCA1, ABCG1, ABCG4,  PXR-response element of CYP3A is recognized ABCG5, ABCG8, CETP, and LPL.78,83–86) Nuclear and transcriptionally activated by CAR.31,128) SREBP regulates HMG-CoA reductase and CYP51,  CAR response elements of CYP2B6 and CYP2C9 which are involved in the cholesterol biosynthesis are transactivated by PXR.129) pathway.102,103) CYP7A1 and CYP8B, which catalyse the  VDRWRXR heterodimer binds to CYP3A4 PXR rate-limiting step in bile acid biosynthesis, are positively response element and promotes gene transcrip- regulatedbyLRH-1androdent'sLXR,andnegatively tion.130) regulated by SHP,73) FXR,65) and PXR.27) The ABC  AHRWARNT heterodimer inhibits estrogen action transporter (ABCA1), which is regulated by LXR, by competitively inhibiting ER alpha binding to PXR, and PPARs, mediates the eŒux of imperfect ERE sites, adjacent to or overlapping cholesterol.74,140) XREs.131) Bile salts are endogenous detergents that assist the ab- 3) Sharing partners sorption and digestion of fats in the intestine; however,  PXR, CAR, VDR, PPAR, and LXR form heter- they can cause hepatotoxicity and colon cancer at high odimer,withRXRtobindDNAandactivategene concentrations.142) FXR represses the Na＋-dependent transcription.19) bile salt uptake transporter NTCP63) as well as the ATP-  AhR, AhRR, and hypoxia-inducible factor 1a dependent bile salt export pump BSEP (ABCB11). The (HIF-1a) form heterodimer with ARNT.15) removal of endogenous and exogenous substances from 4) Functional interactions between NRs andWor TFs the blood circulation and the subsequent secretion into  AhR and ER in complex ways132,133) bile is one of the major functions of the liver. Two  SHP and PXRWCAR19) transport processes, the basolateral uptake from blood  AdipoR1 and AdipoR2 can be modulated by and the apical secretion into bile, play a pivotal role in PPAR and LXR ligands in human atherosclerotic this vectorial transport by hepatocytes. In human lesions and macrophages.134) hepatocytes, the sodium-independent uptake of am- 5) Controlling by other NRs phiphilic organic anions from blood to the liver is  HNF4a controls the expression of PXRWCAR in mediated by diŠerent transport proteins, i.e.,Na＋- the liver.81,135) independent organic anion transporters OATP-C  GR controls the expression of PXRWCAR.19) (SLCO1B1),143,144,145) OATP8 (SLCO1B3),62,145,146) 6) Cofactors OATP-B (SLCO2B1),147) and OAT2 (SLC22A7).148)  PXR-CAR cross-talk determines the net activity of Among them, OATP-C, OATP-A, and OATP8 are guggulsterone against the Cyp2b10 promoter.136) involved in hepatic uptake of bile salts from blood, in  NFAT3 and Estrogen receptor aWb.137) addition to the major Na＋-dependent bile salt uptake  Activated GR enhances CARWPXR-mediated transporter NTCP.149) UGT1A1 regulation with the transcription cofactor PXR, CAR, and VDR respond to secondary bile GRIP1.138) acids (e.g., lithocholic acid) and induce their  Ligand-activated PXR interferes with HNF-4 sig- catabolism, as well as CYP2B6, CYP2C9, CYP3A, and naling by targeting the common coactivator ABC transporters.150) ABC transporters MRP1 PGC-1.110) (ABCC1) and MRP2 (ABCC2) are involved in the  ERRaWPGC-1a-based transcriptional pathway excretion of bile acids from the liver to bile, whereas controls ERRa expression.139) MDR1 (Pgp, ABCB1) and MRP2 are involved in organic anion excretion from the liver to bile. MDR3 Cholesterol and Bile Acid Homeostasis in (ABCB4) and BCRP (MXR, ABCG2) are involved in Human Hepatocytes phosphatidylcholine (PC) and sulfated compound (SC) Cholesterol is synthesized from Acetyl-CoA via excretion, respectively, and MRP3 (ABCC3) is a BA several intermediate steps and is also absorbed from the pump from the liver to blood.28–30) Figure 6 comprehen- diet and reversely transported from peripheral tissues to sively charts the role of NRs in cholesterol and bile acid the liver. It serves as a precursor of steroids such as homeostasis in human hepatocytes. Besides cholesterol corticosteroids, sex hormones, and vitamin D, being and bile acid homeostasis, oxidative stress responses in metabolized to bile acids. The accumulation of excess diŠerent tissues may also help us to elucidate sensor- cholesterol causes atherosclerosis and leads to life- processor pathways and networks. threatening coronary and cerebrovascular diseases.140,141) LXRs, which are bound and activated by the Nuclear Receptors and Regulation of Drug Metabolism Genes 447

Fig. 6. Role of NRs in cholesterol metabolism and biliary balance in human hepatic cells. NRs are indicated by squares (□). Broken lines (--ª) indicate signaling pathways identiˆed in rodents. nSREBP: nuclear SREBP, BA: bile acid, OA: organic anion, OC: organic cation, SC: sulfated compound, NC: neutral compounds, CDCA: chenodeoxycholic acid, LCA: lithocolic acid, PC: phosphatidylcholine. Referenced from Chawla et al.,6) Staudinger et al.,27) Pascussi et al.,28) Holt et al.,65) Repa et al.,74) Goodwin et al.,151) Handschin & Meyer.152)

genes are reported.153–156) Podovinec et al. have devel- In silico Search for Response Elements oped a computer algorithm named NUBIScan,154) which NRs are activated by a multitude of hormones, other is based on weighted nucleotide distribution matrices endogenous substances or xenobiotic chemicals.150–152) and combines scores from both half-sites for NR dimer Those proteins regulate the target genes by contacting binding. Although the prediction is strongly dependent speciˆc response elements on DNA. The identiˆcation on the cut-oŠ scores, the results are likely to include too of these response elements is the ˆrst step toward the many false positives. Roulet et al.155) constructed a elucidating the regulatory mechanisms aŠecting a gene method combining systematic evolution of ligands by andassociateddiseases. exponential enrichment (SELEX) and serial analysis of Many computational approaches to predict DNA gene expression (SAGE) protocols, based on hidden recognition sites for NRs in the regulatory regions of Markov models (HMM). Liu et al.157) introduced Motif 448 Kotoko NAKATA, et al.

Discovery scan (MDscan) that examines the Chip-array- contrast, FRAP experiments detect the bulk rapid, and selected sequences and searches for DNA sequence potentially transient binding of factors and resolve motifs representing the protein-DNA interaction sites events in the sub-second range. Metivier et al.172) with applications to chromatin-immunoprecipitation integrated their ChIP and FRAP data to show the microarray experiments. Comparative genomics and cyclical recruitment of transcription factors, such as phylogenetic approaches were used to identify regula- histone acetyl transferases (HATs), histone deacetylases tory motifs.158–160) (HDACs), histone methyltransferases (HMTs), and Ellrott et al.156) developed an algorithm to scan for Switch sniŠ (SWIWSNF) to the pS2 promoters. binding sites, based on a Markov chain optimization ChIP-chip is a powerful method for identifying method, and achieved 71z success rate for predicting regions of the genome associated with speciˆc proteins, HNF4a binding sites. They suggested that incorporating and analyzing speciˆc changes in a model system under the background information into the model and score various environmental conditions. These associations function would likely improve its prediction accuracy. are crucial for vital cellular functions including gene By combining an implemented promoter recognition transcription, DNA replication and recombination, model, signal processing, artiˆcial neural networks, repair, segregation, chromosomal stability, cell cycle statistics, signal processing techniques, and considera- progression and epigenetic silencing. These approaches tion of G＋C rich or poor regions, Bajic et al. developed oŠer many possibilities for enabling research in molecu- a vertebrate promoter recognition system.161) They lar biology, especially with regard to detailed analysis of developed the Dragon ERE Finder version 2, which was protein and DNA binding in transcription regulation focused on the Estrogen Response Elements (EREs), system. The BioConductor project was organized for andreported83z sensitivity in the prediction of thecollaborativecreationofextensiblesoftwarefor vertebrate genomes,162) Sandelin & Wassermann163) have computational biology and bioinformatics (CBB).173) constructed a ‰exible Hidden Markov Model frame- The purpose of the project is to create a durable and work for predicting nuclear hormone receptor (NHR) ‰exible software development and environmental binding sites and showed that NHRs in Fugu rubripes deployment system that meets these new conceptual, have a signiˆcant cross-regulatory potential. computational, and inferential challenges. The project Tanaka et al. used the Markov chain model to scan provides an online repository for obtaining software, sequences upstream of the annotated transcription start data and metadata, papers, and training materials.173–176) site of 18,406 RefSeq genes,164) for LXR, PPAR, and The transcription factors, their binding sites, nucleo- HNF4a putative response elements (unpublished data). tide distribution matrices and regulated genes and To narrow down the candidate target genes, they related data are provided in the TRANSFAC database scanned the BODYMAP database165) and tried to ˆnd by Wingender et al.177) While the transcription regulato- tissue speciˆc expression patterns. Although the data- ry regions database (TRRD), which is an information base had almost terminated its maintenance and its data resource providing an integrated description of gene were obsolete, such an approach seemed to be useful if transcription regulation, is provided by Kolchanov the tissue-speciˆc gene expression data were constantly et al.178) The Database of Human Transcription Start revised. Sites (DBTSS)179) includes experimentaly determined 5? By using comparative approaches to identify dioxin end clones and information about potential alternative response elements in human, mouse, and rat genomic promoters. It also serves as a means for comparative sequences, Sun et al. reduced the excessive number of promoter analyses. The DNA-binding transcription false-positive, combining gene expression assays and factor database (DBD)180) provides highly accurate chromatin immunoprecipitation assay.166) Sun et al.167) (95z–99z) genome-wide transcription factor predic- have developed a mammalian promoter database tions, based on sequence-speciˆc DNA-binding tran- (MPromDb), that integrates gene promoters with scription factors through homology using proˆle experimentally supported annotation of transcription Hidden Markov models (HMMs) of domain. start sites, cis-regulatory elements, and CpG islands. Advances in genome research have produced huge Both the ChIP assay and ‰uorescence recovery after amounts of information regarding genes and protein photobleaching (FRAP) experiments have been used to structures & functions. Oncogenomics databases of evaluate the transcriptional process kinetically, includ- NCI, NIH, are databases applying DNA microarray- ing the comprehensive and cyclic processes in transcrip- based and other high-throughput techniques.181) Tissue- tional activation of the ERa target pS2 gene promoter in speciˆc gene expression information is included in the human breast cancer MCF-7 cells.168–171) ChIP assays Oncogenomics Normal Tissue Database.182) The data- detect productive associations of promoter sequences base may be useful for narrowing down the computa- with speciˆc transcription factors and require several tional candidate target genes for RE searches. minutes for transcription from one step to another. In Genetic variatios sich such as mutations and single Nuclear Receptors and Regulation of Drug Metabolism Genes 449 nucleotide polymorphisms (SNPs) on NR, RE, or tran- tinuing to collect target genes and to examine the search scription start sites may aŠect the target gene expression system of response elements by combining computa- and the signal pathway. Mutation information from tional and experimental analyses. We hope these eŠorts SWISS-PROTWTrEMBL, several web-based mutation will lead to the development of the new era of drug data resources, and data extracted from the literature metabolism and toxicology research. were assembled in the nuclear Receptor Mutation Database (NRMD).183) For the SNP and HapMap Acknowledgements: The authors thank Dr. Hiroshi search, NCBI dbSNP Homepage,184) HapMap,185) and Nakagawa (Tokyo Institute of Technology) and Dr. M. Japanese SNP Homepage186) are open to be public. The Tien Kuo (University of Texas M.D. Anderson Cancer drug metabolism and toxicity assessment system, which Center) for helpful discussions on the oxidative stress- combined QSAR, ADMEWTox, human cell signaling, mediated induction of ABC transporter genes. In and metabolic pathways & networks with relevant addition, our thanks go to Ms. M. Yukawa and Ms. N. toxicogenomic or other high throughput data,187) is Komiyama for their contribution to preparing the provided by GeneGo Inc., USA. The binding a‹nity ˆgures in this manuscript. database, with 3D structures of target proteins and The work reported in this review article was support- chemicals has been developed,188,189) and binding energy ed in part by the Revolutional Simulation Software calculations using the Fragment Molecular Orbital (RSS21) Project of the Japanese Ministry of Education, Method (FMO) have been examined.190) Culture, Sports, Science and Technology (MEXT). Conclusion References

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