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Biochemical Pharmacology (v.72, #4)

Editorial Advisory Board (pp. iii).

Ah receptor: Dioxin-mediated toxic responses as hints to deregulated physiologic functions by Karl Walter Bock; Christoph Köhle (pp. 393-404).

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and member of the bHLH/PAS (basic Helix-Loop-Helix/Per-Arnt-Sim) family of chemosensors and developmental regulators. It represents a multifunctional molecular switch regulating endo- and xenobiotic metabolism as well as cell proliferation and differentiation. Physiologic functions of the AhR are beginning to be understood, including functions in vascular development, and in detoxification of endo- and xenobiotics. The AhR is also recognized as the culprit for most toxic responses observed after exposure to dioxins and related compounds such as 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). The non-metabolizable AhR agonist TCDD has to be distinguished from the myriad of metabolizable agonists present as dietary contaminants and plant constituents as well as endogenous toxins. The hypothesis is emerging that the diverse tissue-specific, TCDD-mediated toxicities are due to sustained and inappropriate AhR activation leading to deregulated physiologic functions. In support of this hypothesis recent observations in the context of some TCDD-mediated toxic responses are discussed, such as chloracne, cleft palate, thymus involution and in particular carcinogenesis. Major open questions are addressed, such as ligand-independent AhR activation by phosphorylation and the large differences in species-dependent susceptibility to toxic responses. Though important issues remain unresolved, the commentary is intended to stimulate efforts to understand dioxin-mediated toxic responses with emphasis on carcinogenesis in comparison with AhR-mediated physiologic functions.

Keywords: Abbreviations; AhR; aryl hydrocarbon receptor; Arnt; aryl hydrocarbon receptor nuclear translocator; XRE; xenobiotic response element; TCDD; 2,3,7,8-tetrachlorodibenzo-; p; -dioxinAryl hydrocarbon receptor; Dioxin receptor; Physiologic responses; Toxic responses; Carcinogenesis

Apoptotic cell death induction and angiogenesis inhibition in large established medullary thyroid carcinoma xenografts by Ret inhibitor RPI-1 by Giovanna Petrangolini; Giuditta Cuccuru; Cinzia Lanzi; Monica Tortoreto; Sara Belluco; Graziella Pratesi; Giuliana Cassinelli; Franco Zunino (pp. 405-414).

Recent evidence indicates that the success of molecular targeted therapies may depend on the identification of drug targets which are essential for the survival of subsets of tumors. RET oncogenes that have been implicated in the development of thyroid carcinomas are emerging as potential therapeutic targets. In the present study, we investigated the efficacy and the cellular bases of antitumor activity of the indolinone Ret tyrosine kinase inhibitor RPI-1 against large established s.c. TT tumor xenograft, a human medullary thyroid carcinoma (MTC) harboring oncogenic MEN-2A-type RET mutation. Oral treatment with RPI-1 caused growth arrest or regression in 81% treated tumors. Following treatment suspension, tumor inhibition was maintained (51%, P<0.05, 100 days) and cures were achieved in 2/11 mice. In treated tumors, Ret was tyrosine dephosphorylated. Moreover, compared to control tumors, a significant increase in apoptotic cells (210%, P<0.0001), loss of cellularity (47%, P<0.0001) and reduction of microvessel density (36%, P<0.0005) were detected. In vivo effects of RPI-1 were reflected in activation of BAD, cleavage of caspases, apoptotic DNA fragmentation and inhibition of VEGF production observed in in vitro RPI-1-treated TT cells. These findings thus indicate that RPI-1 antitumor effect on the MTC was characterized by apoptosis induction and angiogenesis inhibition. The results, consistent with a dependence on RET oncogene activation for maintenance and survival of MEN2A-type MTC, provide further preclinical rationale for a pharmacological RET-targeted intervention in thyroid cancer.

Keywords: Abbreviations; BID; bis in day; GDNF; glial cell line-derived neurotrophic factor; IHC; immunohistochemistry; MEN-2; multiple endocrine neoplasia 2; MTC; medullary thyroid carcinoma; MVD; microvessel density; PTC; papillary thyroid carcinoma; TUNEL; terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP nick end labeling; TK; tyrosine kinase; TW; tumor weight; TWI; tumor weight inhibitionRet; Thyroid carcinoma; Apoptosis; RPI-1; Tyrosine-kinase inhibitor

Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death by Ritu Aneja; Surya N. Vangapandu; Manu Lopus; Vijaya G. Viswesarappa; Neerupma Dhiman; Akhilesh Verma; Ramesh Chandra; Dulal Panda; Harish C. Joshi (pp. 415-426).

We have previously identified the naturally occurring non-toxic antitussive phthalideisoquinoline alkaloid, noscapine as a tubulin-binding agent that arrests mitosis and induces apoptosis. Here we present high-yield efficient synthetic methods and an evaluation of anticancer activity of halogenated noscapine analogs. Our results show that all analogs display higher tubulin-binding activity than noscapine and inhibit proliferation of human cancer cells (MCF-7, MDA-MB-231 and CEM). Surprisingly, the bromo-analog is ∼40-fold more potent than noscapine in inhibiting cellular proliferation of MCF-7 cells. The ability of these analogs to inhibit cellular proliferation is mediated by cell cycle arrest at the G₂/M phase, in that all analogs except 9-iodonoscapine, caused selective mitotic arrest with a higher efficiency than noscapine followed by apoptotic cell death as shown by immunofluorescence and quantitative FACS analyses. Furthermore, our results reveal the appearance of numerous fragmented nuclei as evidenced by DAPI staining. Thus, our data indicate a great potential of these compounds for studying microtubule-mediated processes and as chemotherapeutic agents for the management of human cancers.

Keywords: Cell cycle; Mitotic arrest; Anticancer; Tubulin-binding

Ras inhibition results in growth arrest and death of androgen-dependent and androgen-independent prostate cancer cells by Shlomit Erlich; Pazit Tal-Or; Ronit Liebling; Roy Blum; Devarajan Karunagaran; Yoel Kloog; Ronit Pinkas-Kramarski (pp. 427-436).

Prostate cancer is one of the most frequently diagnosed cancers in human males. Progression of these tumors is facilitated by autocrine/paracrine growth factors which activate critical signaling cascades that promote prostate cancer cell growth, survival and migration. Among these, Ras pathways have a major role. Here we examined the effect of the Ras inhibitor S- trans, trans-farnesylthiosalicylic acid (FTS), on growth and viability of androgen-dependent and androgen-independent prostate cancer cells.FTS downregulated Ras, inhibited signaling to Akt and reduced the levels of cell-cycle regulatory proteins including cyclin D1, p-RB, E2F-1 and cdc42 in LNCaP and PC3 cells. Consequently the anchorage-dependent and anchorage-independent growth of LNCaP and PC3 cells were inhibited. FTS also induced apoptotic cell death which was inhibited by the broad-spectrum caspases inhibitor, Boc-asp-FMK. Our study demonstrated that androgen-dependent and androgen-independent prostate cancer cells require active Ras for growth and survival. Ras inhibition by FTS results in growth arrest and cell death. FTS may be qualified as a potential agent for the treatment of prostate cancer.

Keywords: Abbreviations; DMEM; Dulbecco modified Eagle's medium; EGF; epidermal growth factor; ERK; extracellular signal-regulated kinase; FGF; fibroblast growth factors; FTS; S-; trans; ,; trans; -farnesylthiosalicylic acid; IGF; insulin-like growth factor; mAb; monoclonal antibody; MAPK; mitogen-activated protein kinase; PBS; phosphate buffered saline; PI3K; phosphoinositide 3-kinase; PKC; protein kinase C; RTK; receptor tyrosine kinase; SDS-PAGE; sodium dodecyl sulfate polyacrylamide gel electrophoresis; TGF; transforming growth factorsRas; Transformation; Signal transduction; Prostate

The angiosuppressive effects of 20(R)- ginsenoside Rg₃ by Patrick Y.K. Yue; Daisy Y.L. Wong; P.K. Wu; P.Y. Leung; N.K. Mak; H.W. Yeung; L. Liu; Zongwei Cai; Zhi-Hong Jiang; T.P.D. Fan; Ricky N.S. Wong (pp. 437-445).

Aberrant angiogenesis is an essential step for the progression of solid tumors. Thus anti-angiogenic therapy is one of the most promising approaches to control tumor growth. In this study, we examined the ability of 20(R)-ginsenoside Rg₃ (Rg₃), one of the active compounds present in ginseng root, to interfere with the various steps of angiogenesis. Rg₃ was found to inhibit the proliferation of human umbilical vein endothelial cells (HUVEC) with an IC₅₀ of 10nM in Trypan blue exclusion assay. Rg₃ (1–10³nM) also dose dependently suppressed the capillary tube formation of HUVEC on the Matrigel in the presence or absence of 20ng/ml vascular endothelial growth factor (VEGF). The VEGF-induced chemoinvasion of HUVEC and ex vivo microvascular sprouting in rat aortic ring assay were both significantly attenuated by Rg₃. In addition, Rg₃ (150 and 600nM) remarkably abolished the basic fibroblast growth factor (bFGF)-induced angiogenesis in an in vivo Matrigel plug assay. The Matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, which play an important role in the degradation of basement membrane in angiogenesis and tumor metastasis present in the culture supernatant of Rg₃-treated aortic ring culture were found to decrease in their gelatinolytic activities. Taken together, these data underpin the anti-tumor property of Rg₃ through its angiosuppressive activity.

Keywords: Anti-angiogenesis; Ginsenosides; Rg; ₃; HUVEC

KR-62980: A novel peroxisome proliferator-activated receptor γ agonist with weak adipogenic effects by Kwang Rok Kim; Jeong Hyung Lee; Seung Jun Kim; Sang Dal Rhee; Won Hoon Jung; Sung-Don Yang; Sung Soo Kim; Jin Hee Ahn; Hyae Gyeong Cheon (pp. 446-454).

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is the target for the anti-diabetic drugs including thiazolidinediones. We report here the identification and characterization of a novel PPARγ agonist KR-62980. KR-62980 acted as a selective PPARγ agonist in transactivation assay with an EC₅₀ of 15nM. In fully differentiated 3T3-L1 adipocytes, KR-62980 induced [³H]-deoxyglucose uptake in a concentration-dependent manner in the presence of insulin. KR-62980 was weakly adipogenic with little induction of aP2 mRNA, and was able to antagonize the adipogenic effects of rosiglitazone in C3H10T1/2 cells. In vivo pharmacokinetic profile of KR-62980 revealed that the compound exhibited good oral bioavailability of 65% with a terminal elimination half-life of 2.5h in the rat. Treatment of high fat diet-induced C57BL/6J mice with KR-62980 for 14 days reduced plasma glucose levels with little side effects with regard to weight gain, cardiac hypertrophy and hepatotoxicity. These results suggest that KR-62980 acts as a selective PPARγ modulator with anti-hyperglycemic activity, and that the mechanism of actions of KR-62980 appears to be different from that of rosiglitazone with improved side effect profiles.

Keywords: Abbreviations; AF-2; activation function-2; LBD; ligand binding domain; PPARγ; peroxisome proliferator-activated receptor γ; RT-PCR; reverse transcriptase-polymerase chain reactionPPARγ; Adipogenesis; High fat diet-induced model; Glucose-lowering; Weight gain; Pharmacokinetics

Bucillamine induces glutathione biosynthesis via activation of the transcription factor Nrf2 by Ana M. Wielandt; Valeska Vollrath; Marcelo Farias; Jose Chianale (pp. 455-462).

The properties of bucillamine, a synthetic antioxidant, have been attributed mainly to the donation of thiol groups to glutathione (GSH). We recently demonstrated that glutamate–cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme of GSH biosynthesis, and the multidrug-resistance-associated protein 2 (Mrp2/MRP2) are coordinately induced in response to xenobiotic through the activation of the antioxidant-response element (ARE) by nuclear factor-erythroid 2 p45-related factor (Nrf2). We tested the hypothesis that bucillamine and its oxidized metabolite SA 981 also activate the Nrf2 pathway, thereby increasing glutathione biosynthesis in human HepG2 and murine Hepa 1–6 hepatoma cell lines, through the induction of the GCLC enzyme as well as the Mrp2/MRP2 transporter, which mediates the excretion of glutathione and its conjugates from hepatocytes. Both bucillamine and SA 981 produced a significant dose-dependent increase in the mRNA levels of Mrp2/MRP2 and GCLC after 24h. The levels of the transcription factor Nrf2 in the nuclei were maximal at 3h, remained elevated at 6h, and decreased to control values at 24h in both cell lines. Moreover, both bucillamine and SA 981 significantly increased the expressions of Mrp2/MRP2 and GCLC proteins in both cell lines. Finally, in both cell lines, bucillamine and SA 981 increased the GSH content two- to three-fold. These results demonstrate that bucillamine and SA 981 activate the ARE–ARE pathway increasing the expression of ARE-driven genes such as those of GCLC and Mrp2/MRP2. The role of bucillamine as a chemopreventive agent against cancer remains to be elucidated.

Keywords: Bucillamine; Glutamate–cysteine ligase (GCL); Multidrug-resistance-associated protein 2(Mrp2/MRP2); Glutathione (GSH); Nuclear factor-erythroid 2 p45-related factor (Nrf2)Abbreviations; ARE; antioxidant-response element; DMEM; Dulbecco's modified Eagle's medium; DTT; dithiothreitol; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; GCL; glutamate–cysteine ligase; GCLC; GCL catalytic subunit; GSH; glutathione; GSSG; oxidized glutathione; GST; glutathione; S; -transferase; MRP; multidrug-resistance-associated protein; Nrf2; nuclear factor-erythroid 2 p45-related factor; PMSF; phenylmethylsulphonyl fluoride; ROS; reactive oxygen species; RT-PCR; reverse-transcription polymerase chain reaction

Suppressive effects of antimycotics on tumor necrosis factor-α-induced CCL27, CCL2, and CCL5 production in human keratinocytes by Naoko Kanda; Shinichi Watanabe (pp. 463-473).

Antimycotic agents are reported to improve cutaneous symptoms of atopic dermatitis or psoriasis vulgaris. Keratinocytes in these lesions excessively produce chemokines, CCL27, CCL2, or CCL5 which trigger inflammatory infiltrates. Tumor necrosis factor-α (TNF-α) induces production of these chemokines via activating nuclear factor-κB (NF-κB). We examined in vitro effects of antimycotics on TNF-α-induced CCL27, CCL2, and CCL5 production in human keratinocytes. Antimycotics ketoconazole and terbinafine hydrochloride suppressed TNF-α-induced CCL27, CCL2, and CCL5 secretion and mRNA expression in keratinocytes in parallel to the inhibition of NF-κB activity while fluconazole was ineffective. Anti-prostaglandin E₂ (PGE₂) antiserum or antisense oligonucleotides against PGE₂ receptor EP2 or EP3 abrogated inhibitory effects of ketoconazole and terbinafine hydrochloride on TNF-α-induced NF-κB activity and CCL27, CCL2, and CCL5 production, indicating the involvement of endogenous PGE₂ in the inhibitory effects. Prostaglandin H₂, a precursor of PGE₂ can be converted to thromboxane A₂. Ketoconazole, terbinafine hydrochloride and thromboxane A₂ synthase (EC 5.3.99.5) inhibitor, carboxyheptyl imidazole increased PGE₂ release from keratinocytes and reduced that of thromboxane B₂, a stable metabolite of thromboxane A₂. Carboxyheptyl imidazole also suppressed TNF-α-induced NF-κB activity and CCL27, CCL2, and CCL5 production. These results suggest that ketoconazole and terbinafine hydrochloride may suppress TNF-α-induced NF-κB activity and CCL27, CCL2, and CCL5 production by increasing PGE₂ release from keratinocytes. These antimycotics may suppress thromboxane A₂ synthesis and redirect the conversion of PGH₂ toward PGE₂. These antimycotics may alleviate inflammatory infiltration in atopic dermatitis or psoriasis vulgaris by suppressing chemokine production.

Keywords: Antimycotic; Keratinocyte; Prostaglandin E; ₂; CCL27; CCL2; CCL5

The influence of various structural parameters of semisynthetic sulfated polysaccharides on the P-selectin inhibitory capacity by Juliane Fritzsche; Susanne Alban; Ralf J. Ludwig; Simone Rubant; Wolf-Henning Boehncke; Gabriele Schumacher; Gerd Bendas (pp. 474-485).

Selectin-mediated leukocyte rolling along the endothelium is of key importance for maintaining the cellular immune response. The anti-inflammatory activities of heparin have partly been related to inhibition of P-selectin binding. Heparin, however, suffers from its heterogeneous variable structure, the animal origin and multiple in vivo effects. As P-selectin is a promising target for anti-inflammatory approaches, we focused on P-selectin inhibition by other sulfated polysaccharides and compared them with six heparins. We examined 15 structurally defined semisynthetic sulfated glucans, non-animal-derived from the linear glucans phycarin, curdlan or pullulan. The derivatives gradually differ in their degree of sulfation, molecular weight, and glycosidic linkage. The inhibitory capacity was analysed in a parallel plate flow chamber, detecting the rolling of U937 cells on P-selectin layers.Unfractionated heparins displayed variabilities between different preparations. Considering fractionated heparins, exceeding of a minimal mass is essential for activity. Comparing the glucan sulfates, charge density is the most important parameter for P-selectin binding. Highly sulfated derivatives are excellent inhibitors, the reduced cell binding up to 16.2±6.4% strongly exceeded the heparin activities. Molecular weight is of minor effects, while glycosidic backbone linkage holds certain importance.To check the P-selectin inhibition in vivo, heparin and one phycarin sulfate were tested using intravital microscopy of microvasculature in mice. Both compounds significantly reduced the rolling fractions of activated platelets on endothelium as effective as a blocking P-selectin antibody.Our study indicates that semisynthetic glucan sulfates with optimal structures block P-selectin excellently and might become promising candidates for anti-inflammatory drugs to replace heparin for certain applications.

Keywords: Abbreviations; BCECF-AM; 2′,7′-bis(2-carboxyethyl)-5,6-carboxyfluorescein-acetoxymethyl ester; CurS; curdlan sulfate; DP; degree of polymerisation; DS; degree of sulfation; ESI-MS; electrospray ionisation mass spectrometry; LMWH; low molecular weight heparin; mAb; monoclonal antibody; MMWH; medium molecular weight heparin; MW; molecular weight; PhyS; phycarin sulfate; PGE; ₁; prostaglandin E; ₁; PSGL-1; P-selectin glycoprotein ligand-1; PulS; pullulan sulfate; RT; room temperature; sLex; sialyl Lewis; ^X; TRAP; thrombin receptor agonist peptide; U937; human monocytic cell line; UFH; unfractionated heparin; VLMWH; very low molecular weight heparinCell adhesion; Heparin; Inflammation; Polysaccharides; P-selectin

Modulation of cadmium induced alterations in murine thymocytes by piperine: Oxidative stress, apoptosis, phenotyping and blastogenesis by Neelima Pathak; Shashi Khandelwal (pp. 486-497).

Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medicinal use in Indian medicine. It is known to exhibit a variety of biological activities which include anti-pyretic, anti-inflammatory, anti-depressant, hepatoprotective and antitumor. Its immunomodulatory role has so far been limited to humoral response. The influence of piperine on murine thymocytes, immunocompromised by cadmium has been reported by us in this investigation. The various biochemical parameters such as oxidative stress markers (ROS and GSH), Bcl-2 protein expression, mitochondrial membrane potential, caspase-3 activity, DNA damage, blastogenesis and T lymphocyte phenotypes were determined. Cadmium (25μM) induced apoptosis earliest at 6h. Alterations in ROS and GSH preceded mitochondrial membrane depolarization and caspase-3 activation followed by apoptosis. The phenotypic changes occurred at 18h and blastogenesis at 72h. Various conc. of piperine (1, 10 and 50μg/ml) when added along with Cd (25μM) from 1.5 to 72h, caused a dose and time dependent amelioration in all the cellular events mentioned above. Modulation of oxidative stress has earlier been reported to reduce Cd induced apoptosis in murine lymphocytes. Inhibition of the ROS production and replenishment of GSH by piperine, may in part be responsible for the suppression of downstream cascade of events, i.e. apoptosis, blastogenesis and T lymphocyte phenotyping. The study clearly demonstrated the anti-oxidative, anti-apoptotic, and restorative ability against cell proliferative mitogenic response and phenotypic alterations by piperine, suggesting its therapeutic usefulness in immunocompromised conditions.

Keywords: Piperine; Murine thymocytes; Apoptosis; Oxidative stress; Phenotyping; Blastogenesis

Stereoselectivity of 8-OH-DPAT toward the serotonin 5-HT_1A receptor: Biochemical and molecular modeling study by Joanna Dabrowska; Michal Brylinski (pp. 498-511).

The great majority of pharmacological investigations of 5-HT_1A receptors’ reactivity has been performed using racemic 8-OH-DPAT, therefore the biochemical as well as behavioral profiles of both 8-OH-DPAT enantiomers are not circumstantiated. In the biochemical study capability of racemic 8-OH-DPAT (0.05, 0.1mg/kg s.c.) and its counterparts R-8-OH-DPAT (0.05, 0.1mg/kg s.c.) and S-8-OH-DPAT (0.05, 0.1mg/kg s.c.) to influence 5-HT synthesis rate in rats’ prefrontal cortex, hypothalamus, hippocampus and brainstem was evaluated by HPLC/ED technique. Biochemical results are supported by the exhaustive computational study of possible differences between R- and S-enantiomer toward the 5-HT_1A receptor. A reliable 3D model of the rat 5-HT_1A receptor was constructed from the amino acid sequence using the crystal structure of bovine rhodopsin as a structural template. The structure of the receptor model was validated through docking studies and molecular dynamics simulations that gave results consistent with experimental data. Docking studies and the dynamics of ligand–receptor complexes emphasized different profiles of both enantiomers at the molecular level. The results of both biochemical and computational studies confirmed that R-enantiomer in contrast to S-8-OH-DPAT acts as full and potent agonist, whilst racemic form may display similar pharmacological profile to R-8-OH-DPAT.

Keywords: Abbreviations; 5-HT; serotonin; 5-HT; _1A; serotonin 1A subtype receptor; 8-OH-DPAT; 8-hydroxy-2-(di-; n; -propylamino)-tetralin; ASA; accessible solvent area; BS; brainstem; CA; hippocampus; DRN; dorsal raphe nucleus; ECL; extracellular loop; GPCR; G-protein-coupled receptor; HP; hypothalamus; HPLC/ED; high-pressure liquid chromatography with electrochemical detection; ICL; intracellular loop; l; -5-HTP; 5-hydroxytryptophan; MD; molecular dynamics; MM; molecular mechanics energy minimization; MRN; median raphe nucleus; PFC; prefrontal cortex; TMH; transmembrane helix5-HT; _1A; receptor; 5-HT synthesis; R; -8-OH-DPAT; S; -8-OH-DPAT; Stereoselectivity; Molecular dynamics

Alterations in transporter expression in liver, kidney, and duodenum after targeted disruption of the transcription factor HNF1α by J.M. Maher; A.L. Slitt; T.N. Callaghan; X. Cheng; C. Cheung; F.J. Gonzalez; C.D. Klaassen (pp. 512-522).

The transcription factor hepatocyte nuclear factor 1α (HNF1α) is involved in regulation of glucose metabolism and transport, and in the expression of several drug and bile acid metabolizing enzymes. Targeted disruption of the HNF1α gene results in decreased Cyp1a2, and Cyp2e1 expression, and increased Cyp4a1 and Cyp7a1 expression, suggesting these enzymes are HNF1α target genes. Since hepatic metabolism can be coordinately linked with drug and metabolite transport, this study aims to demonstrate whether HNF1α regulates expression of a variety of organic anion and cation transporters through utilization of an HNF1α-null mouse model. Expression of 32 transporters, including members of the Oat, Oatp, Oct, Mrp, Mdr, bile acid and sterolin families, was quantified in three different tissues: liver, kidney, and duodenum. The expression of 17 of 32 transporters was altered in liver, 21 of 32 in kidney, and 6 of 32 in duodenum of HNF1α-null mice. This includes many novel observations, including marked downregulation of Oats in kidney, as well as upregulation of many Mrp and Mdr family members in all three tissues. These data indicate that disruption of HNF1α causes a marked attenuation of several Oat and Oatp uptake transporters in liver and kidney, and increased expression of efflux transporters such as Mdrs and Mrps, thus suggesting that HNF1α is a central mediator in regulating hepatic, renal, and intestinal transporters.

Keywords: Abbreviations; Cyp; cytochrome P450; HNF; hepatocyte nuclear factor; MODY-3; maturity onset diabetes of the young type 3; Mrp; multidrug resistance-associated protein; Mdr; multidrug resistance protein; Oat; organic anion transporter; Oct; organic cation transporter; NIDDM; non-insulin dependent diabetes mellitusHepatocyte nuclear factor 1 alpha; Gene expression; Transcription factor; Transporter; ABC; SLC; Gene regulation

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Biochemical Pharmacology (v.72, #4)