Skip to main content
SpringerLink
Log in

High-throughput screening for analysis of in vitro toxicity

  • Chapter
Molecular, Clinical and Environmental Toxicology

Part of the book series: Experientia Supplementum ((EXS,volume 99))

Abstract

The influence of combinatorial chemistry and high-throughput screening (HTS) technologies in the pharmaceutical industry during the last 10 years has been enormous. However, the attrition rate of drugs in the clinic due to toxicity during this period still remained 40-50%. The need for reduced toxicity failure led to the development of early toxicity screening assays. This chapter describes the state of the art for assays in the area of genotoxicity, cytotoxicity, carcinogenicity, induction of specific enzymes from phase I and II metabolism, competition assays for enzymes of phase I and II metabolism, embryotoxicity as well as endocrine disruption and reprotoxicity. With respect to genotoxicity, the full Ames, Ames II, Vitotox™, GreenScreen GC, RadarScreen, and non-genotoxic carcinogenicity assays are discussed. For cytotoxicity, cellular proliferation, calcein uptake, oxygen consumption, mitochondrial activity, radical formation, glutathione depletion as well as apoptosis are described. For high-content screening (HCS), the possibilities for analysis of cytotoxicity, micronuclei, centrosome formation and phospholipidosis are examined. For embryotoxicity, endocrine disruption and reprotoxicity alternative assays are reviewed for fast track analysis by means of nuclear receptors and membrane receptors. Moreover, solutions for analyzing enzyme induction by activation of nuclear receptors, like AhR, CAR, PXR, PPAR, FXR, LXR, TR and RAR are given.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  1. Brown D, Superti-Furga G (2003) Rediscovering the sweet spot in drug discovery. Drug Discov Today 8: 1067–1077

    PubMed  Google Scholar 

  2. DiMasi JA (2001) Risks in new drug development: Approval success rates for investigational drugs. Clin Pharmacol Ther 69: 297–307

    PubMed  CAS  Google Scholar 

  3. Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3: 711–715

    PubMed  CAS  Google Scholar 

  4. Caldwell GW, Ritchie DM, Masucci JA, Hageman W, Yan Z (2001) The new pre-clinical paradigm: Compound optimization in early and late phase drug discovery. Curr Top Med Chem 1: 353–366

    PubMed  CAS  Google Scholar 

  5. Schuster D, Laggner C, Langer T (2005) Why drugs fail-A study on side effects in new chemical entities. Curr Pharm Des 11: 3545–3559

    PubMed  CAS  Google Scholar 

  6. Smith DA, Schmid EF (2006) Drug withdrawals and the lessons within. Curr Opin Drug Discov Dev 9: 38–46

    CAS  Google Scholar 

  7. Cuatrecasas P (2006) Drug discovery in jeopardy. J Clin Invest 116: 2837–2842

    PubMed  CAS  Google Scholar 

  8. Gagne D, Balaguer P, Demirpence E, Chabret C, Trousse F, Nicolas JC, Pons M (1994) Stable luciferase transfected cells for studying steroid receptor biological activity. J Biolumin Chemilumin 9: 201–209

    PubMed  CAS  Google Scholar 

  9. Naylor LH (1999) Reporter gene technology: The future looks bright. Biochem Pharmacol 58: 749–757

    PubMed  CAS  Google Scholar 

  10. Dijkema R, Schoonen WGEJ, Teuwen R, Struik van der E, Ries de RJH, Kar SAT, Olijve W (1998) Human progesterone receptor A and B isoforms in CHO cells. I. Stable transfection of receptor and receptor-responsive reporter genes: Transcription modulation by (anti)progestagens. J Steroid Biochem Mol Biol 64: 140–156

    Google Scholar 

  11. Balaguer P, Boussioux A-M, Demirpence E, Nicolas JC (2001) Reporter cell lines are useful tools for monitoring biological activity of nuclear receptor ligands. Luminescence 16: 153–158

    PubMed  CAS  Google Scholar 

  12. Willemsen P, Scippo ML, Kausel G, Figueroa J, Maghuin-Rogister G, Martial JA, Muller M (2004) Use of reporter cell lines for detection of endocrine-disrupter activity. Anal Bioanal Chem 378: 655–663

    PubMed  CAS  Google Scholar 

  13. Lai C, Jiang X, Li X (2006) Development of luciferase reporter-based cell assays. Assay Drug Dev Technol 4: 307–315

    PubMed  CAS  Google Scholar 

  14. Stratowa C, Himmler A, Czernilofsky AP (1995) Use of a luciferase reporter system for characterizing G-protein-linked receptors. Curr Opin Biotech 6: 574–581

    CAS  Google Scholar 

  15. Durocher Y, Perret S, Thibaudeau E, Gaumond MH, Kamen A, Stocco R, Abramovitz M (2000) A reporter gene assay for high-throughput screening of G-protein-coupled receptors stably or transiently expressed in HEK293 EBNA cells grown in suspension culture. Anal Biochem 284: 316–326

    PubMed  CAS  Google Scholar 

  16. Gabriel D, Vernier M, Pfeifer MJ, Dasen B, Tenaillon L, Bouhelal R (2003) High throughput technologies for direct cyclic AMP measurement. Assay Drug Dev Technol 1: 291–303

    PubMed  CAS  Google Scholar 

  17. Kunapuli P, Ransom R, Murphy KL, Pettibone D, Kerby J, Grimwood S, Zuck P, Hodder P, Lacson R, Hoffman I et al (2003) Development of an intact cell reporter gene b-lactamase assay for G protein-coupled receptors for high-throughput screening. Anal Biochem 314: 16–29

    PubMed  CAS  Google Scholar 

  18. Hemmilä IA, Hurskainen P (2002) Novel detection strategies for drug discovery. Drug Discov Today 7: 150–156

    Google Scholar 

  19. Cómez-Henz A, Aguilar-Caballos MP (2007) Modern analytical approaches to high throughput screening. Trends Anal Chem 26: 171–182

    Google Scholar 

  20. Ames BN, Lee FD, Durston WE (1973) An improved bacterial test system for the detection and classification of mutagens and carcinogens. Proc Natl Acad Sci USA 70: 782–786

    PubMed  CAS  Google Scholar 

  21. McCann J, Choi E, Yamasaki E, Ames BN (1975) Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc Natl Acad Sci USA 72: 5135–5139

    PubMed  CAS  Google Scholar 

  22. Miller B, Pötter-Locher F, Seelbach A, Stopper H, Utesch D, Madle S (1998) Evaluation of the in vitro micronuclei test as an alternative to the in vitro chromosomal aberration assay: Position of the GUM working group on the in vitro micronucleus test. Mutat Res 410: 81–116

    PubMed  CAS  Google Scholar 

  23. McGregor JT, Casciano D, Müller L (2000) Strategies and testing methods for identifying mutagenic risks. Mutat Res 455: 3–20

    Google Scholar 

  24. Richard AM (1998) Structure-based methods for predicting mutagenicity and carcinogenicity: Are we there yet? Mutat Res 400: 493–507

    PubMed  CAS  Google Scholar 

  25. Cariello NE, Wilson JD, Britt BH, Wedd DJ, Burlinson B, Gombar V (2002) Comparison of the computer programs DEREK and TOPKAT to predict bacteria mutagenicity. Mutagenesis 17: 321–329

    PubMed  CAS  Google Scholar 

  26. Greene N (2002) Computer systems for the prediction of toxicity: An update. Adv Drug Deliv Rev 54: 417–431

    PubMed  CAS  Google Scholar 

  27. Mitchell AD (2000) in vitro genetic toxicity testing. In: SC Gad (eds): In vitro Toxicology, 2nd edn. CRC Press, Boca Raton, 94–127

    Google Scholar 

  28. Mortelmans K, Zeiger E (2000) The Ames Salmonella/microsome mutagenicity assay. Mutat Res 455: 29–60

    PubMed  CAS  Google Scholar 

  29. Musatov, SA, Anisimov VN, André V, Vigreux C, Godard T, Gauduchon P, Sichel F (1998) Modulatory effects of melatonin on genotoxic response of reference mutagens in the Ames test and the comet assay. Mutat Res 417: 75–84

    PubMed  CAS  Google Scholar 

  30. Jemnitz K, Veres Z, Torok G, Toth E, Vereckey L (2004) Comparative study in the Ames test of benzo[a]pyrene and 2-aminoanthracene activation using rat hepatic S9 and hepatocytes following in vivo or in vitro activation. Mutagenesis 19: 245–250

    PubMed  CAS  Google Scholar 

  31. Flückiger-Isler S, Baumeister M, Braun K, Gervais V, Nasler-Nguyen N, Reimann R, Van Gompel J, Wunderlich HG, Engerhardt G (2004) Assessment of the performance of the Ames IITM assay: A collaborative study with 19 coded compounds. Mutat Res 558: 181–189

    PubMed  Google Scholar 

  32. Piegorsch WW, Simmons SJ, Margolin BH, Zeiger E, Gidrol XM, Gee P (2000) Statistical modeling and analyses of a base-specific Salmonella mutagenicity assay. Mutat Res 467: 11–19

    PubMed  CAS  Google Scholar 

  33. Lelie van der D, Regniers L, Borremans B, Provoost A, Verschaeve L (1997) The VITOTOX® test, an SOS bioluminescence Salmonella typhimurium test to measure genotoxicity kinetics. Mutagenesis 20: 449–454

    Google Scholar 

  34. Verschaeve L, Van Gompel J, Thilemans L, Regniers L, Vanparys P, van der Lelie D (1999) VITO TOX® bacterial genotoxicity and toxicity test for the rapid screening of chemicals. Environ Mol Mutagen 33: 240–248

    PubMed  CAS  Google Scholar 

  35. Van Gompel J, Woestenborghs F, Beerens D, Mackie C, Cahill PA, Knight AW, Billinton N, Tweats DJ, Walmsley RM (2005) An assessment of the utility of the yeast GreenScreen assay in pharmaceutical screening. Mutagenesis 20: 449–454

    PubMed  Google Scholar 

  36. Westerink WMA, Stevenson JCR, Schoonen WGEJ (2009) Evaluation of the Vitotox and Radarscreen assay for the rapid early assessment of genotoxicity in the research phase of drug development. Mutat Res (submitted)

    Google Scholar 

  37. Jacobson-Kram D, Contrera JF (2007) Genetic toxicity assessment: Employing the best science for human safety evaluation part I: Early screening for potential human mutagens. Toxicol Sci 96: 16–20

    PubMed  CAS  Google Scholar 

  38. Kirkland D, Pfuhler S, Tweats D, Aardema M, Corvi R, Darroudi F, Elhajouji A, Glatt H, Hastwell P, Hayashi M et al (2007) How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: Report of an ECVAM Workshop. Mutat Res 628: 31–55

    PubMed  CAS  Google Scholar 

  39. Tweats DJ, Scott AD, Westmoreland C, Carmichael PL (2007) Determination of genetic toxicity and potential carcinogenicity in vitro-Challenges post the seventh amendment to the European cosmetics directive. Mutagenesis 22: 5–13

    PubMed  CAS  Google Scholar 

  40. Pastink A, Eeken JCJ, Lohman PHM (2001) Genomic integrity and the repair of double-strand DNA breaks. Mutat Res 480-481: 37–50

    PubMed  CAS  Google Scholar 

  41. Clever B, Interthal H, Schmuckli-Maurer J, King J, Sigrist M, Heyer WF (1997) Recombinational repair in yeast: Functional interactions between Rad51 and Rad54 proteins. EMBO J 16: 2535–2544

    PubMed  CAS  Google Scholar 

  42. Sonoda E, Sasaki MS, Buerstedde J-M, Bezzubova O, Shinohara A, Ogawa H, Takata M, Yamaguchi-Iwai Y, Takeda S (1998) Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death. EMBO J 17: 598–608

    PubMed  CAS  Google Scholar 

  43. Arbel A, Zenvirth D, Simchen G (1999) Sister chromatid-based DNA repair is mediated by RAD54, not by DMC1 or TID1. EMBO J 18: 2648–2658

    PubMed  CAS  Google Scholar 

  44. Dronkert MLG, Beverloo HB, Johnson RD, Hoeijmakers JHJ, Jasin M, Kanaar R (2000) Mouse RAD54 affects DNA double-strand break repair and sister chromatid exchange. Mol Cell Biol 20: 3147–3156

    PubMed  CAS  Google Scholar 

  45. Billinton N, Barker MG, Michel CE, Knight AW, Heyer W-D, Goddard NJ, Fielden PR, Walmsley RM (1998) Development of a green fluorescent protein reporter for a yeast genotoxicity biosensor. Biosens Bioelectr 13: 831–838

    CAS  Google Scholar 

  46. Cahill PA, Knight AW, Billington N, Barker MG, Walsh L, Keenan PO, Williams CV, Tweats DJ, Walmsley RM (2004) The GreenScreen® genotoxicity assays: A screening validation programme. Mutagenesis 19: 105–119

    PubMed  CAS  Google Scholar 

  47. Knight AW, Billinton N, Cahill PA, Scott A, Harvey JS, Roberts KJ, Tweats DJ, Keenan PO, Walmsley RM (2007) An analysis of results from 305 compounds tested with the yeast RAD54-GFP genotoxicity assay (GreenScreen GC)-including relative predictivity of regulatory tests and rodent carcinogenesis and performance with autofluorescent and coloured compounds. Mutagenesis 22: 409–416

    PubMed  CAS  Google Scholar 

  48. Cole GM, Schild D, Lovett ST, Mortimer RK (1987) Regulation of RAD54-and RAD52-lacZ gene fusions in Saccharomyces cerevisiae in response to DNA damage. Mol Cell Biol 7: 1078–1084

    PubMed  CAS  Google Scholar 

  49. Averbeck D, Averbeck S (1994) Induction of the genes RAD54 and RNR2 by various damaging agents in Saccharomyces cerevisiae. Mutat Res 315: 123–138

    PubMed  CAS  Google Scholar 

  50. Joosten HFP, Acker FAA, Dobbelsteen van den DJ, Horbach GJMJ, Krajnc EI (2004) Genotoxicity of hormonal steroids. Toxicol Lett 151: 113–134

    PubMed  CAS  Google Scholar 

  51. Hastwell PW, Chai LL, Roberts KJ, Webster ThW, Harvey JS, Rees RW, Walmsley RM (2006) High-specificity and high-sensititvity genotoxicity assessment in a human cell line: Validation of the GreenScreen HC GADD45a-GFP genotoxicity assay. Mutat Res 607: 160–175

    PubMed  CAS  Google Scholar 

  52. Jover R, Pondosa X, Castell JV, Gómez-Lechón MJ (1992) Evaluation of the cytotoxicity of ten chemicals on human cultured hepatocytes: Predictability of human toxicity and comparison with rodent cell culture systems. Toxicol In Vitro 6: 47–52

    CAS  Google Scholar 

  53. Okey AB, Roberts EA, Harper PA, Denison MS (1986) Induction of drug-metabolizing enzymes: Mechanisms and consequences. Clin Biochem 19: 132–141

    PubMed  CAS  Google Scholar 

  54. Marcillat O, Zhang Y, Davies KJ (1989) Oxidative and non-oxidative mechanisms in the inactivaHigh-tion of cardiac mitochondrial electron transport chain components by doxorubicin. Biochem J 259: 181–189

    PubMed  CAS  Google Scholar 

  55. Zhou S, Starkov A, Froberg MK, Leino RL, Wallace KB (2001) Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 61: 771–777

    PubMed  CAS  Google Scholar 

  56. Olson RD, Mushlin PS, Brenner DE, Fleischer S, Cusak BJ, Chang BK, Boucek RJ (1988) Doxorubicin cardiotoxicity may be caused by its metabolite doxorubicinol. Proc Natl Acad Sci USA 85: 3585–3589

    PubMed  CAS  Google Scholar 

  57. Mordente A, Minotti G, Martorana GE, Silvestrini A, Giardina B, Meucci E (2003) Anthracycline secondary alcohol metabolite formation in human or rabbit heart: Biochemical aspects and pharmacologic implications. Biochem Pharmacol 66: 989–998

    PubMed  CAS  Google Scholar 

  58. Fries de R, Mitsuhashi M (1995) Quantification of mitogen induced human lymphocyte proliferation: Comparison of Alamar BlueTM assay to 3H-thymidine incorporation assay. J Clin Lab Anal 9: 89–95

    PubMed  Google Scholar 

  59. Gieni RS, Li Y, HayGlass KT (1995) Comparison of 3H-thymidine incorporation with MTT-and MTS-based bioassays for human and murine IL-2 and IL-4 analysis. Tetrazolium assays provide markedly enhanced sensitivity. J Immunol Methods 187: 85–93

    PubMed  CAS  Google Scholar 

  60. Wagner U, Burkhardt E, Failing K (1999) Evaluation of canine lymphocyte proliferation: Comparison of three different colorometric methods with the 3H-thymidine incorporation assay. Vet Immunol Immunopathol 70: 151–159

    PubMed  CAS  Google Scholar 

  61. Nagahama T, Sawada M, Gonzalez FJ, Yokoi T, Kamataki T (1996) Stable expression of human CYP2E1 in Chinese hamster cells: High sensitivity to N,N-dimethylnitrosamine in cytotoxicity testing. Mutat Res 360: 181–186

    Google Scholar 

  62. Blaheta RA, Franz M, Auth MKH,Wenisch HJC, Markus BH (1991) A rapid non-radioactive fluorescence assay for the measurement of both cell number and proliferation. J Immunol Methods 142: 199–206

    PubMed  CAS  Google Scholar 

  63. Lydon MJ, Keeler KD, Thomas DB (1980) Vital DNA coloring and cell sorting by flow microfluorometry. J Cell Physiol 102: 175–181

    PubMed  CAS  Google Scholar 

  64. Richards WL, Song MK, Krutsch H, Everts RP, Marsden E, Thorgeirsson SS (1985) Measurement of cell proliferation using Hoechst 33342 for the rapid semiautomated microfluorometric determination of chromatin DNA. Exp Cell Res 159: 235–246

    PubMed  CAS  Google Scholar 

  65. Dhar S, Nygren P, Liminga G, Sundstrom G, de la Torre M, Nilsson K, Larsson R (1998) Relationship between cytotoxic drug response patterns and activity of drug efflux transporters mediating multidrug resistance. Eur J Pharmacol 346: 315–322

    PubMed  CAS  Google Scholar 

  66. Marbeuf-Gueye G, Salerno M, Quidu P, Garnier-Suillerot A (2000) Inhibition of the P-glycoprotein and multidrug resistance protein efflux of anthracyclines and calceinacetoxymethyl ester by PAK-104P. Eur J Pharmacol 391: 207–216

    PubMed  CAS  Google Scholar 

  67. Fernandez-Checa JC, Kaplowitz N (1990) The use of monochlorobimane to determine hepatic GSH levels and synthesis. Anal Biochem 190: 212–219

    PubMed  CAS  Google Scholar 

  68. Stevenson D, Wokosin D, Girkin J, Grant MH (2002) Measurement of the intracellular distribution of reduced glutathione in cultured rat hepatocytes using monochlorobimane and confocal laser scanning microscopy. Toxicol In Vitro 16: 609–619

    PubMed  CAS  Google Scholar 

  69. Young PR, ConnorsWhite AL, Dzido GA (1994) Kinetic analysis of the intracellular conjugation of monochlorbimane by IC-21 murine macrophage glutathione-S-transferase. Biochim Biophys Acta 1201: 461–465

    PubMed  Google Scholar 

  70. Gabriel C, Camins A, Sureda FX, Aquirre L, Escubedo E, Pallàs M, Camarasa J (1997) Determination of nitric oxide generation in mammalian neurons using dichlorofluorescin diacatate and flow cytometry. J Pharmacol Toxicol Methods 38: 93–98

    PubMed  CAS  Google Scholar 

  71. Sanner BM, Meder U, Zidek W, Tepel M (2002) Effects of glucocorticoids on generation of reactive oxygen species in platelets. Steroids 67: 715–719

    PubMed  CAS  Google Scholar 

  72. Soliman MK, Mazzio E, Soliman KFA (2002) Levodopa modulating effects of inducible nitric oxide synthase and reactive oxygen species in glioma cells. Life Sci 72: 185–198

    PubMed  CAS  Google Scholar 

  73. Berridge MV, Tan AS, McCoy KD, Wang R (1996) The biochemical and cellular basis of cell proliferation assays that use tetrazolium salts. Biochemica 4: 14–19

    Google Scholar 

  74. Andrews MJ, Garle MJ, Clothier RH (1997) Reduction of the new tetrazolium dye, Alamar BlueTM, in cultured rat hepatocytes and liver fractions. ATLA 25: 641–653

    Google Scholar 

  75. Nakayama GR, Caton MC, Nova MP, Parandoosh Z (1997) Assessment of the Alamar Blue assay for cellular growth and viability in vitro. J Immunol Methods 240: 205–208

    Google Scholar 

  76. O’Brien J, Wilson I, Orton T, Pognan F (2000) Investigation of the Alamar Blue (resazurin) fluo rescent dye for the assessment of mammalian cell cytotoxicity. Eur J Biochem 267: 5421–5426

    PubMed  CAS  Google Scholar 

  77. Slaughter MR, Bugelski PJ, O’Brien PJ (1999) Evaluation of Alamar Blue reduction for in vitro assay of hepatocyte toxicity. Toxicol In Vitro 13: 567–569

    CAS  Google Scholar 

  78. Hynes J, Hill R, Papkovsky DB (2006) The use of a fluorescence-based oxygen uptake assay in the analysis of cytotoxicity. Toxicol In Vitro 20: 785–792

    PubMed  CAS  Google Scholar 

  79. Chan JH, Harminder SD, Powell-Richards A, Jones DRE, Harris IM (2001) Effect of ABO blood group mismatching on corneal epithelial cells: An in vitro study. Br J Ophthalmol 85: 1104–1109

    PubMed  CAS  Google Scholar 

  80. Hannah R, Beck M, Moravec R, Riss T (2001) CellTiter-GloTM luminescent cell viability assay: A sensitive and rapid method for determining cell viability. Promega Cell Notes 2: 11–13

    Google Scholar 

  81. Germain MA, Hatton A, Williams S, Matthews JB, Stone MH, Fisher J, Ingham E, (2003) Comparison of the cytotoxicity of clinically relevant cobalt-chromium and alumina ceramic wear particles in vitro. Biomaterials 24: 469–479

    PubMed  CAS  Google Scholar 

  82. Schoonen WG, de Roos JA, Westerink WM, Debiton E (2005) Cytotoxic effects of 110 reference compounds on HepG2 cells and for 60 compounds on HeLa, ECC-1 and CHO cells. II. Mechanistic assays on NAD(P)H, ATP and DNA contents. Toxicol In Vitro 19: 491–503

    PubMed  CAS  Google Scholar 

  83. Schoonen WG, Westerink WM, de Roos JA, Debiton E (2005) Cytotoxic effects of 100 reference compounds on Hep G2 and HeLa cells and of 60 compounds on ECC-1 and CHO cells. I. Mechanistic assays on ROS, glutathione depletion and calcein uptake. Toxicol In Vitro 19: 505–516

    PubMed  CAS  Google Scholar 

  84. Ekwall B, Sandström B (1978) Combined toxicity to HeLa cells of 30 drug pairs, studied by a twodimensional microtitre method. Toxicol Lett 2: 285–292

    CAS  Google Scholar 

  85. Ekwall B, Sandström B (1978) Improved use of the metabolic inhibition test to screen combined drug toxicity to HeLa cells-preliminary study of 61 drug pairs. Toxicol Lett 2: 293–298

    CAS  Google Scholar 

  86. Ekwall B, Johansson A (1980) Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. I. Comparative in vitro cytotoxicity of 27 drugs. Toxicol Lett 5: 299–307

    PubMed  CAS  Google Scholar 

  87. Clemedson C, McFarlane-Abdulla E, Andersson M, Barile B, Calleja MC, Chesné C, Clothier R, Cottin M, Curren R, Dierickx PJ et al (1996) MEIC evaluation of acute systemic toxicity. Part II. in vitro results from 68 toxicity assays used to test the first 30 reference chemicals and a comparative cytotoxicity analysis. ATLA 24: 273–311

    Google Scholar 

  88. Clemedson C, Ekwall B (1999) Overview of the MEIC results: I. The in vitro-in vitro evaluation. Toxicol In Vitro 13: 657–663

    CAS  Google Scholar 

  89. Clemedson C, Blaauboer B, Castell J, Prieto P, Ristyelli L, Vericat JA, Wendel A (2006) ACuteTox-Optimation and pre-validation of an in vitro test strategy for predicting human acute toxicity. ALTEX 23 Suppl: 254–258

    Google Scholar 

  90. Clemedson C, Kolman A, Forsby A (2007) The integrated acute systemic toxicity traject (ACuteTox) for the optimisation and validation of alternative in vitro tests. Altern Lab Anim 35: 33–38

    PubMed  CAS  Google Scholar 

  91. Thabrew MI, Hughes RD, McFarlane IG (1997) Screening of hepatoprotective plant components using a HepG2 cell cytotoxicity assay. J Pharmacol 49: 1132–1135

    CAS  Google Scholar 

  92. Ekwall B (1980) Toxicity to HeLa cells of 205 drugs as determined by the metabolic inhibition test supplemented by microscopy. Toxicology 17: 273–295

    PubMed  CAS  Google Scholar 

  93. Ekwall B (1980) Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. III. Lethal action to man of 43 drugs related to the HeLa cell toxicity of the lethal drug concentrations. Toxicol Lett 5: 319–331

    PubMed  CAS  Google Scholar 

  94. Ekwall B (1980) Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. II. Drug toxicity in the MIT-24 system compared with mouse and human lethal dosage of 52 drugs. Toxicol Lett 5: 309–317

    PubMed  CAS  Google Scholar 

  95. Ekwall B, Bondesson I, Castell JV, Gómez-Lechón MJ, Hellberg S, Högberg J, Jover R, Pondosa X, Romert L, Stenberg K, Walum E (1989) Cytotoxicity evaluation of the first ten MEIC chemicals: Acute lethal toxicity in man predicted by cytotoxicity in five cellular assays and by oral LD50 tests in rodents. ATLA 17: 83–100

    Google Scholar 

  96. Clothier RH, Hulme LM, Smith M, Balls M, (1987) Comparison of the in vitro cytotoxicities and acute in vivo toxicities of 59 chemicals. Mol Toxicol 1: 571–577

    PubMed  CAS  Google Scholar 

  97. Bondesson I, Ekwall B, Hellberg S, Romert L, Stenberg K, Walum E (1989) MEIC-A new international multicenter project to evaluate the relevance to human toxicity of in vitro cytotoxicity tests. Cell Biol Toxicol 5: 331–347

    PubMed  CAS  Google Scholar 

  98. Barile FA, Dierickx PJ, Kristen U (1994) in vitro toxicity testing for prediction of acute human toxicity. Cell Biol Toxicol 10: 155–162

    PubMed  CAS  Google Scholar 

  99. Pondosa X, Núñez C, Castell JV, Gómez-Lechón MJ (1997) Evaluation of the cytotoxic effects of MEIC chemicals 31-50 on primary culture of rat hepatocytes and hepatic and non-hepatic cell lines. ATLA 25: 423–436

    Google Scholar 

  100. Scheers EM, Ekwall B, Dierickx PJ (2001) in vitro long-term cytotoxicity testing of 27 MEIC chemicals on Hep G2 cells and comparison with acute human toxicity data. Toxicol In Vitro 15: 153–161

    PubMed  CAS  Google Scholar 

  101. Ekwall B (1999) Overview of the final MEIC results: II The in vitro-in vivo evaluation, including the selection of a practical battery of cell tests for prediction of acute lethal blood concentrations in humans. Toxicol in Vitro 13: 665–673

    CAS  Google Scholar 

  102. Rosenkranz HS, Cunningham AR (2000) The high production volume chemical challenge program: The rodent LD50 and its possible replacement. ATLA 28: 271–277

    Google Scholar 

  103. O’Brien MA, Daily WJ, Hesselberth E, Moravec RA, Scurria MA, Klaubert DH, Bulleit RF, Wood KV (2005) Homogeneous, bioluminescent protease assay: Caspase 3 as a model. J Biomol Screen 10: 137–148

    PubMed  CAS  Google Scholar 

  104. Liu D, Li C, Chen Y, Burnett C, Liu XY, Downs S, Colllins RD, Hawegir J (2004) Nuclear transport of proinflammatory transcription factors is required for massive liver apoptosis induced by bacterial lipopolysaccharide. J Biol Chem 279: 48434–48442

    PubMed  CAS  Google Scholar 

  105. Parkinson A (2003) Biotransformation and xenobiotics. In: CD Klaassen and JB Watkins (eds): Casarett & Doull’s Essentials of Toxicology. McGraw-Hill, New York, 71–97.

    Google Scholar 

  106. Meyer UA (2000) Pharmacogenetics and adverse drug interactions. Lancet 356: 1667–1671

    PubMed  CAS  Google Scholar 

  107. Bao H, Vepakomma M, Sarkar MA (2002) Benzo[a]pyrene exposure induces CYP1A1 activity and expression in human endometrial cells. J Steroid Biochem Mol Biol 81: 37–45

    PubMed  CAS  Google Scholar 

  108. Huang WY, Chatterjee N, Chanock S, Dean M, Yeager M, Schoen RE, Hou LF, Berndt SI, Yadavalli S, Johnson CC, Hayes RB (2005) Microsomal epoxide hydrolase polymorphisms and risk for advanced colorectal adenoma. Cancer Epidemiol Biomarkers Prev 14: 152–157

    PubMed  CAS  Google Scholar 

  109. Uno S, Dalton TP, Shertzer HG, Genter MB, Warshawsky D, Talaska G, Nebert DW (2001) Benzo[a]pyrene-induced toxicity: Paradoxical protection in Cyp1a1(-/-) knockout mice having increased hepatic BaP-DNA adduct levels. Biochem Biophys Res Commun 289: 1049–1056

    PubMed  CAS  Google Scholar 

  110. Seppen J, Bosma PJ, Goldhoorn BG, Bakker CTM, Chowdhury JR, Chowdhury NR, Jansen PLM, Oude Elferink RPJ (1994) Discrimination between Crigler najjar Type I and II by expression of mutant bilirubin uridine phosphate-glucuronosyltransferase. J Clin Invest 94: 2385–2391

    PubMed  CAS  Google Scholar 

  111. Aono S, Adachi Y, Uyama E, Yamada Y, Keino H, Nanno T, Koiwai O, Sato H (1995) Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert’s syndrome. Lancet 345: 958–959

    PubMed  CAS  Google Scholar 

  112. Hewitt NJ, Hewitt P (2004) Phase I and II enzyme characterization of two sources of HepG2 cell lines. Xenobiotica 34: 243–256

    PubMed  CAS  Google Scholar 

  113. Rodriguez-Antona C, Donato MT, Boobis A, Edwards RJ, Watts PS, Castell JV, Gomez-Lechon MJ (2002) Cytochrome P450 expression in human hepatocytes and hepatoma cell lines: Molecular mechanisms that determine lower expression in cultured cells. Xenobiotica 32: 505–520

    PubMed  CAS  Google Scholar 

  114. Wilkening S, Stahl F, Bader A (2003) Comparison of primary human hepatocytes and hepatoma cell line HepG2 with regard to their biotransformation properties. Drug Metab Disp 31: 1035–1042

    CAS  Google Scholar 

  115. Gomez-Lechon MJ, Donato MT, Castell JV, Jover R (2004) Human hepatocytes in primary culture: The choice to investigate drug metabolism in man. Curr Drug Metab 5: 443–462

    PubMed  CAS  Google Scholar 

  116. Westerink WMA, Schoonen WGEJ (2007) Phase I enzyme levels in cryopreserved primary human hepatocytes and HepG2 cells and their induction in HepG2 cells. Toxicol In Vitro 21: 1581–1591.

    PubMed  CAS  Google Scholar 

  117. Westerink WMA, Schoonen WGEJ (2007) Phase II enzyme levels in HepG2 cells and cryopreserved human primary human hepatocytes and their induction in HepG2 cells. Toxicol In Vitro 21: 1592–1602

    PubMed  CAS  Google Scholar 

  118. Köhle C, Bock KW (2007) Coordinate regulation of phase I and II xenobiotic metabolism by the Ah receptor and Nrf2. Biochem Pharmacol 73: 1853–1862

    PubMed  Google Scholar 

  119. Fletcher N, Wahlström D, Lundberg R, Nilsson CB, Nilsson KC, Stockling K, Hellmold H, Håkansson H (2005) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the mRNA expression of critical genes associated with cholesterol metabolism, bile acid biosynthesis, and bile transport in rat liver: A microarray study. Toxicol Appl Pharmacol 207: 1–24

    PubMed  CAS  Google Scholar 

  120. Adachi J, Mori Y, Matsui S, Takigami H, Fujino J, Kitagawa H, Miller CA III, Kato T, Saeki K, Matsuda T (2001) Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. J Biol Chem 276: 31475–31478

    PubMed  CAS  Google Scholar 

  121. Runge D, Kohler C, Kostrubsky VE, Jager D, Lehmann T, Runge DM, May U, Stolz DB, Strom SC, Fleig WE, Michalopoulos GK (2000) Induction of cytochrome P450 (CYP)1A1, CYP1A2, and CYP3A4 but not of CYP2C9, CYP2C19, multidrug resistance (MDR-1) and multidrug resistance associated protein (MRP-1) by prototypical inducers in human hepatocytes. Biochem Biophys Res Commun 273: 333–341

    PubMed  CAS  Google Scholar 

  122. Yueh MF, Kawahara M, Raucy J (2005) Cell-based high-throughput bioassays to assess induction and inhibition of CYP1A enzymes. Toxicol In Vitro 19: 275–287

    PubMed  CAS  Google Scholar 

  123. Bock KW, Kohle C (2004) Coordinate regulation of drug metabolism by xenobiotic nuclear receptors: UGTs acting together with CYPs and glucuronide transporters. Drug Metab Rev 36: 595–615

    PubMed  CAS  Google Scholar 

  124. Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA (2002) Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62: 638–646

    PubMed  CAS  Google Scholar 

  125. Mankowski DC, Ekins S (2003) Prediction of human drug metabolizing enzyme induction. Curr Drug Metab 4: 381–391

    PubMed  CAS  Google Scholar 

  126. Xie, W, Yeuh MF, Radominska-Pandya A, Saini SP, Negishi Y, Bottroff BS, Cabrera GY, Tukey RH, Evans RM (2003) Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Proc Natl Acad Sci USA 100: 4150–4155

    PubMed  CAS  Google Scholar 

  127. Moore JT, Moore LB, Maglich JM, Kliewer SA (2003) Functional and structural comparison of PXR and CAR. Biochim Biophys Acta 1619: 235–238

    PubMed  CAS  Google Scholar 

  128. Waxman DJ (1999) P450 gene induction by structurally diverse xenochemicals: Central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369: 11–23

    PubMed  CAS  Google Scholar 

  129. Wei P, Zhang J, Dowhan DH, Han Y, Moore DD (2002) Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. Pharmacogenomics J 2: 117–126

    PubMed  CAS  Google Scholar 

  130. Repa JJ, Turley SD, Lobaccaro JMA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ (2000) Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289: 1524–1529

    PubMed  CAS  Google Scholar 

  131. Gupta S, Stravitz RT, Dent P, Hylemon PB (2001) Down-regulation of cholesterol 7a-hydroxylase (CYP7A1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-jun N-terminal kinase pathway. J Biol Chem 276: 15816–15822

    PubMed  CAS  Google Scholar 

  132. Anderson SP, Dunn C, Laughter A, Yoon L, Swanson C, Stulnig TM, Steffensen KR, Chandraratna RAS, Gustafsson Jå, Corton JC (2004) Overlapping transcriptional programs regulated by the nuclear receptors peroxisome proliferator-activated receptor a, retinoic X receptor and liver X receptor in mouse liver. Mol Pharmacol 66: 1440–1452

    PubMed  CAS  Google Scholar 

  133. Goodwin B, Watson MA, Kim H, Miao J, Kemper JK, Kliewer SA (2003) Differential regulation of rat and human CYP7A1 by the nuclear orphan receptor liver X receptor a. Mol Endocrinol 17: 386–394

    PubMed  CAS  Google Scholar 

  134. Wilson TM, Lambert MH, Kliewer SA (2001) Peroxisome proliferator-activated receptor g and metabolic disease. Annu Rev Biochem 70: 341–367

    Google Scholar 

  135. O’Brien PJ, Irwin W, Diaz D, Howard-Cofield E, Krejsa CM, Slaughter MR, Gao B, Kaludercic N, Angeline A, Bernardi P, Brain P, Hougham C (2006) High concordance of drug-induced human hepatotoxicity with in vitro cytotoxicity measured in a novel cell-based model using high content screening. Arch Toxicol 80: 580–604

    PubMed  CAS  Google Scholar 

  136. Xu JJ (2007) High content screening with primary rat hepatocytes. Lecture Symposium on: High Content Screening for Toxicity (Informa). Le Meridian, Vienna, Austria, 28 June 2007

    Google Scholar 

  137. Vanparys P (2007) New models for toxicity testing. 2nd Conference of Predictive Human Toxicity and ADME Toxicity Studies. Brussels, Belgium, 25-26 January 2007

    Google Scholar 

  138. Herrera G, Diaz L, Martinez-Romero A, Gomes A, Villamon E, Callaghan RC, O’Connor JE (2007) Cytomics: A multiparametric, dynamic approach to cell research. Toxicol In Vitro 21: 176–182

    PubMed  CAS  Google Scholar 

  139. Giuliano KA, Haskins JR, Taylor DL (2003) Advances in high content screening for drug discovery. Assay Drug Dev Technol 1: 565–577

    PubMed  CAS  Google Scholar 

  140. Haney SA, LaPan P, Pan J, Zhang J (2006) High-content screening moves to the front of the line. Drug Discov Today 11: 889–894

    PubMed  CAS  Google Scholar 

  141. Houck KA, Kavlock RJ (2008) Understanding mechanisms of toxicity: Insights from drug discovery research. Toxicol Appl Pharmacol 277: 163–178

    Google Scholar 

  142. Diaz D, Scott A, Carmichael P, Shi W, Costales C (2007) Evaluation of an automated in vitro micronucleus assay in CHO-K1 cells. Mutat Res 630: 1–13

    PubMed  CAS  Google Scholar 

  143. McMillian MK, Grant ER, Zhong Z, Parker JB, Li L, Zivin RA, Burczynski ME, Johnson MD (2001) Nile red binding to HepG2 cells: An improved assay for in vitro studies of hepatosteatosis. In Vitro Mol Tox 14: 177–190

    CAS  Google Scholar 

  144. Reasor MJ, Hastings KL, Ulrich RG (2006) Drug-induced phospholipidosis: Issues and future directions. Exp Opin Drug Safety 5: 567–583

    CAS  Google Scholar 

  145. Fujimara H, Dekura E, Kurabe M, Shimazu N, Koitabashi M, Toriumi W (2007) Cell-based fluorescence assay for evaluation of new-drugs potential for phospholipidosis in an early stage of drug development. Exp Toxicol Pathol 58: 375–382

    Google Scholar 

  146. Nioi P, Perry BK, Wang EJ, Gu YZ, Snyder RD (2007) in vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies. Toxicol Sci 99: 162–173

    PubMed  CAS  Google Scholar 

  147. Fingerhut MA, Halperin WE, Marlow DA, Piacitelli LA, Honchar PA, Sweeney MH, Greife AL, Dill PA, Steenland K, Suruda AJ (1991) Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N Engl J Med 324: 212–218

    PubMed  CAS  Google Scholar 

  148. Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H (1991) Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet 338: 959–964

    PubMed  CAS  Google Scholar 

  149. Zober A, Messerer P, Huber P (1990) Thirty-four-year mortality follow-up of BASF employees exposed to 2,3,7,8-TCDD after the 1953 accident. Int Arch Occup Environ Health 62: 139–157

    PubMed  CAS  Google Scholar 

  150. Vanden Heuvel PJ (1999) Peroxisome proliferator-activated receptors (PPARS) and carcinogenesis. Toxicol Sci 47: 1–8

    Google Scholar 

  151. Stewart JR, Artime MC, O’Brian CA (2003) Resveratrol: A candidate nutritional substance for prostate cancer prevention. J Nutr 133: 2440S–2443S

    PubMed  CAS  Google Scholar 

  152. Galati G, O’Brien PJ (2004) Potential toxicity of flavonoids and other dietary phenolics: Significance for their chemopreventive and anticancer properties. Free Radic Biol Med 37: 287–303

    PubMed  CAS  Google Scholar 

  153. Moon YJ, Wang X, Morris ME (2006) Dietary flavanoids: Effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro 20: 187–210

    PubMed  CAS  Google Scholar 

  154. Chen I, McDougal A,Wang F, Safe S (1998) Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. Carcinogenesis 19: 1631–1639

    PubMed  CAS  Google Scholar 

  155. Kim YS, Milner JA (2005) Targets for indole-3-carbinol in cancer prevention. J Nutr Biochem 16: 65–73

    PubMed  CAS  Google Scholar 

  156. Meijer L, Sheare J, Bettayeb K, Ferandin Y (2006) Diversity of intracellular mechanisms underlying the anti-tumor properties of indirubins. In: L Meijer, N Guyard, L Skaltsounis, G Eisenbrand (eds): Indirubin, The Red Shade of Indigo. Life in Progress Editions, Roscoff, 235–246

    Google Scholar 

  157. Westerink WMA, Stevenson JCR, Schoonen WGEJ (2007) CYP1A induction and species differences between human HepG2 and rat H4IIE cells. Toxicol Lett 172 Suppl 1: S98

    Google Scholar 

  158. Morimura K, Cheung C, Ward JM, Reddy JK, Gonzalez FJ (2005) Differential susceptibility of mice humanized for peroxisome proliferator-activated receptor a to Wy-14,643-induced liver tumorigenesis. Carcinogenesis 27: 1074–1080

    PubMed  Google Scholar 

  159. Crespi CL, Miller VP (1999) The use of heterologously expressed drug metabolizing enzymes-State of the art and prospects for the future. Pharmacol Ther 84: 121–131

    PubMed  CAS  Google Scholar 

  160. Crespi CL, Miller VP, Penman BW (1997) Microtiter plate assays for inhibition of human, drugmetabolizing cytochromes P450. Anal Biochem 248: 188–190

    PubMed  CAS  Google Scholar 

  161. Miller VP, Stresser DM, Blanchard AP, Turner S, Crespi CL (2000) Fluorometric high-throughput screening for inhibitors of cytochrome P450. Ann NY Acad Sci 919: 26–32

    PubMed  CAS  Google Scholar 

  162. Stresser DM, Turner SD, Blanchard AP, Miller VP, Crespi CL (2002) Cytochrome P450 fluorometric substrates: Identification of isoform-selective probes for rat CYP2D2 and human CYP3A4. Drug Metab Disp 30: 845–852

    CAS  Google Scholar 

  163. Nakajima M, Sakata N, Ohashi N, Kume T, Yokoi T (2002) Involvement of multiple UDP-glucuronosyltransferase 1A isoforms in glucuronidation of 5-(4’-hydroxyphenyl)-5-phenylhydantoin in human liver microsomes. Drug Metab Disp 30: 1250–1256

    CAS  Google Scholar 

  164. Kurkela M, Garcia-Horsman JA, Luukkanen L, Mörsky S, Taskinen J, Baumann M, Kostianen R, Hirvonen J, Finel M (2003) Expression and characterization of recombinant human UDP-glucuronosyltransferases (UGTs). J Biol Chem 278: 3536–3544

    PubMed  CAS  Google Scholar 

  165. Collier AC, Tingle MD, Keelan JA, Paxton JW, Mitchell MD (2000) A highly sensitive fluorescent microplate method for the determination of UDP-glucuronosyl transferase activity in tissues and placental cell lines. Drug Metab Disp 28: 1184–1186

    CAS  Google Scholar 

  166. Uchaipichat V, Mackenzie PI, Guo X-H, Gardner-Stephen D, Galetin A, Houston JB, Miners JO (2004) Human UDP-glucuronosyltransferases: Isoform selectivity and kinetics of 4-methylumbelliferone and 1-naphthol glucuronidation, effects of organic solvents, and inhibition by diclofenac and probecenid. Drug Metab Disp 32: 413–423

    CAS  Google Scholar 

  167. Broudy MI, Crespi CL, Patten CJ (2001) A sensitive fluorometric high throughput inhibition assay for human UDP glucuronosyl transferase (UGT) 1A1. Poster presentation: BD Biosciences, Property of Becton, Dickinson and Company

    Google Scholar 

  168. Trubetskoy OV, Finel M, Kurkela M, Fitzgerald M, Peters NR, Hoffman FM, Trubetskoy VS (2007) High throughput screening assay for UDP-glucuronosyltransferase 1A1 glucuronidation profiling. Assay Drug Dev Technol 5: 343–354

    PubMed  CAS  Google Scholar 

  169. Wu JJ, Huang DB, Pang KR, Hsu S, Tyring SK (2005) Thalidomide: Dermatological indications, mechanisms of action and side-effects. Br J Dermatol 153: 254–273

    PubMed  CAS  Google Scholar 

  170. Genschow E, Spielmann, H, Scholz G, Seiler A, Brown N, Piersma A, Brady M, Clemann N, Huuskonen H, Paillard F et al (2002) The ECVAM international validation study on in vitro embryotoxicity tests: Results of the definitive phase and evaluation of prediction models. ATLA 30: 151–176

    PubMed  CAS  Google Scholar 

  171. Piersma AH (2004) Validation of alternative methods for developmental toxicity testing. Toxicol Lett 149: 147–153

    PubMed  CAS  Google Scholar 

  172. Piersma AH (2006) Alternative methods for developmental toxicity testing. Basics Clin Pharmacol Toxicol 98: 427–431

    CAS  Google Scholar 

  173. Piersma AH, Janer G, Wolterink G, Bessems JGM, Hakkert BC, Slob W (2008) Quantitative extrapolation of in vitro whole embryo culture embryotoxicity data to developmental toxicity in vivo using the benchmark dose approach. Toxicol Sci 101: 91–100

    PubMed  CAS  Google Scholar 

  174. Jansen MS, Nagel SC, Miranda PJ, Lobenhofer EK, Afshari CA, McDonnell DP (2004) Shortchain fatty acids enhance nuclear receptor activity through mitogen activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci USA 101: 7199–7204

    PubMed  CAS  Google Scholar 

  175. Tabb MM, Blumberg B (2006) New modes of action of endocrine-disrupting chemicals. Mol Endocrinol 20: 475–482

    PubMed  CAS  Google Scholar 

  176. Campbell LR, Dayton DH, Sohal GS (1986) Neural tube defects: A review of human and animal studies on the etiology of neural tube defects. Teratology 34: 171–187

    PubMed  CAS  Google Scholar 

  177. Sulik KK, Dehart DB, Rogers JM, Chernoff N (1995) Teratogenicity of low doses of all-trans retinoic acid in presomite mouse embryos. Teratology 51: 398–403

    PubMed  CAS  Google Scholar 

  178. Arnhold T, Elmazar MMA, Nau H (2002) Prevention of vitamin A teratogenesis by phytol or phytanic acid results from reduced metabolism of retinol to the teratogenic metabolite, all-trans retinoic acid. Toxicol Sci 66: 274–282

    PubMed  CAS  Google Scholar 

  179. Wang Z, Brown DD (1993) Thyroid hormone-induced gene expression program for amphibian tail resorption. J Biol Chem 268: 16270–16278

    PubMed  CAS  Google Scholar 

  180. Brown DD, Wang Z, Furlow JD, Kanamori A, Schwartman RA, Remo BF, Pinder A (1996) The thyroid hormone-induced tail resorption program during Xenopus laevis metamorphosis. Proc Natl Acad Sci USA 93: 1924–1929

    PubMed  CAS  Google Scholar 

  181. Hollowell JG Jr, Hannon WH (1997) Teratogen update: Iodine deficiency, a community teratogen. Teratology 55: 389–405

    PubMed  CAS  Google Scholar 

  182. Yang XF, Xu J, Hou XH, Guo HL, Hao LP, Yao P, Liu LG, Sun XF (2006) Developmental toxic effects of chronic exposure to high doses of iodine in the mouse. Reprod Toxicol 22: 725–730

    PubMed  CAS  Google Scholar 

  183. Sanders JP, van der Geyten S, Kaptein E, Darras VM, Kühn ER, Leonard JL, Visser TJ (1997) Characterization of a propylthiouracil-insensitive type 1 iodothyronine deiodinase. Endocrinology 138: 5153–5160

    PubMed  CAS  Google Scholar 

  184. Köhrle J (2000) The deiodinase family: Selenoenzymes regulating thyroid hormone availability and action. Cell Mol Life Sci 57: 1853–1863

    PubMed  Google Scholar 

  185. Barrington EJW (1975) An Introduction to General Comparative Endocrinology, 2nd edn. Clarendon Press, Oxford, 147–184

    Google Scholar 

  186. Huang H, Marsh-Armstrong N, Brown DD (1999) Metamorphosis is inhibited in transgenic Xenopus laevis tadpoles that overexpress type III deiodinase. Proc Natl Acad Sci USA 96: 962–967

    PubMed  CAS  Google Scholar 

  187. Glincer D (1984) Thyroid dysfunction in the pregnant patients. In: LJ DeGroot, PR Larsen, G Hennemann (eds): The Thyroid and Its Diseases. Wiley, New York

    Google Scholar 

  188. Jaber M, Robinson SW, Missale C, Caron MG (1996) Dopamine receptors and brain function. Neuropharmacology 35: 1503–1519

    PubMed  CAS  Google Scholar 

  189. Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PPA (1994) VII. International union of pharmacology classification of receptors for 5-hydroxttryptamine (serotonin). Pharmacol Rev 46: 157–203

    PubMed  CAS  Google Scholar 

  190. Shuey DL, Sadler TW, Lauder JM (1992) Serotonin as a regulator of craniofacial morphogenesis site specific malformations following exposure to serotonin uptake inhibitors. Teratology 46: 367–378

    PubMed  CAS  Google Scholar 

  191. Jurand A, Martin LVH (1990) Teratogenic potential of two neurotropic drugs, haloperidol and dextromoramide, tested on mouse embryos. Teratology 42: 45–54

    PubMed  CAS  Google Scholar 

  192. Van Cauteren H, Vandenberghe J, Marsboom R (1986) Protective activity of ketanserin against serotonin-induced embryotoxicity and teratogenicity in rats. Drug Dev Res 8: 179–185

    Google Scholar 

  193. Huuskonen H (2005) New models and molecular markers in evaluation of developmental toxicity. Toxicol Appl Pharmacol 207 Suppl: 495–500

    Google Scholar 

  194. Hill AJ, Teraoka H, Heideman W, Peterson RE (2005) Zebrafish as a model vertebrate for investigating chemical toxicity. Toxicol Sci 86: 6–19

    PubMed  CAS  Google Scholar 

  195. Hershberger LG, Shipley, EG, Meyer RK (1953) Myometric activity of 19-nortestosterone and other steroids determined by modified levator and muscle method. Proc Soc Exp Biol Med 83: 175–180

    PubMed  CAS  Google Scholar 

  196. Ashley J, Lefevre PA (2000) Preliminary evaluation of the major protocol variables for the Hershberger castrated male rat assay for the detection of androgens, antiandrogens, and metabolic modulators. Regul Toxicol Pharmacol 31: 92–105

    Google Scholar 

  197. Allen A, Doisy EA (1923) An ovarian hormone. Preliminary report on its location, extraction and partial purification and action in test animals. J Am Med Assoc 81: 819–821

    CAS  Google Scholar 

  198. Wakeling AE (1995) Use of pure antioestrogens to elucidate the mode of action of oestrogens. Biochem Pharmacol 49: 1545–1549

    PubMed  CAS  Google Scholar 

  199. Van der Vies J, de Visser J (1983) Endocrinological studies with desogestrel. Arzneimittelforschung 33: 231–236

    PubMed  Google Scholar 

  200. McPhail MK (1934) The assay of progestin. J Physiol 83: 145–156

    PubMed  CAS  Google Scholar 

  201. Bergink EW, van Meel F, Turpijn EW, van der Vies J (1983) Binding of progestagens to receptor proteins in MCF-7 cells. J Steroid Biochem 19: 1563–1570

    PubMed  CAS  Google Scholar 

  202. Schoonen WGEJ, Joosten JWH, Kloosterboer HJ (1995) Effects of two classes of progestagens, pregnane and 19-nortestosterone derivatives, on cell growth of human breast tumor cells. I. MCF-7 cell lines. J Steroid Biochem Mol Biol 55: 423–437

    PubMed  CAS  Google Scholar 

  203. Schoonen WGEJ, Dijkema R, Ries de RJH, Wagenaars JL, Joosten JWH, de Gooyer ME, Deckers GH, Kloosterboer HJ (1998) Human progesterone receptor A and B isoforms in CHO cells. II. Comparison of binding, transactivation and ED50 values of several synthetic (anti)progestagens in vitro in CHO and MCF-7 cells and in vivo in rabbits and rats. J Steroid Biochem Mol Biol 64: 157–170

    PubMed  CAS  Google Scholar 

  204. Schoonen WGEJ, Ries de RJH, Joosten JWH, Mathijssen-Mommers GJW, Kloosterboer HJ (1998) Development of a high throughput in vitro bioassay for the assessment of potencies of steroids for the progesterone receptor with a luciferase reporter system in CHO cells. Anal Biochem 261: 222–224

    PubMed  CAS  Google Scholar 

  205. Sonneveld E, Riteco JAC, Jansen HJ, Pieterse B, Brouwer A, Schoonen WG, van der Burg B (2006) Comparison of in vitro and in vivo screening models for androgenic and estrogenic activities. Toxicol Sci 89: 173–187

    PubMed  CAS  Google Scholar 

  206. Legler J, van den Brink CE, Brouwer A, Murk AJ, van der Saag PT, Vethaak AD, van der Burg B (1999) Development of a stably transfected estrogen receptor-mediated luciferase reporter gene assay in the human T47D breast cancer cell line. Toxicol Sci 48: 55–66

    PubMed  CAS  Google Scholar 

  207. Blankvoort BMG, de Groene EM, van Meeteren-Kreikamp AP, Witkamp RF, Rodenburg RJT, Aarts JMMJG (2001) Development of an androgen reporter gene assay (AR-LUX) utilizing a human cell line with an endogenously regulated androgen receptor. Anal Biochem 298: 93–102

    PubMed  CAS  Google Scholar 

  208. Wilson VS, Bobseine K, Gray LE Jr, (2004) Development and characterization of a cell line that stably expresses an estrogen-responsive luciferase reporter for the detection of estrogen receptor agonist and antagonists. Toxicol Sci 81: 69–77

    PubMed  CAS  Google Scholar 

  209. Wilson VS, Bobseine K, Lambright CR, Gray LE Jr, (2002) A novel cell line, MDA-kb2, that stably expresses an androgen-and glucocorticoid-responsive reporter for the detection of hormone receptor agonists and antagonists. Toxicol Sci 66: 69–81

    PubMed  CAS  Google Scholar 

  210. Wong SP, Li J, Shen P, Gong Y, Yap SP, Yong EL (2007) Ultrasensitive cell-based bioassay for the measurement of global estrogenic activity of flavonoid mixtures revealing additive, restrictive, and enhanced actions in binary and higher order combinations. Assay Drug Dev Technol 5: 355–362

    PubMed  CAS  Google Scholar 

  211. Bovee TFH, Helsdingen RJR, Rietjens IMCM, Keijer J, Hoogenboom RLAP (2004) Rapid yeast estrogen bioassays stably expressing human estrogen receptors a and b, and green fluorescent proteIn: A comparison of different compounds with both receptor types. J Steroid Biochem Mol Biol 91: 99–109

    PubMed  CAS  Google Scholar 

  212. Bovee TFH, Helsdingen RJR, Hamers ARM, Van Duursen MBM, Nielen MWF, Hoogenboom RLAP (2007) A new highly specific and robust yeast androgen bioassay for the detection of agonists and antagonists. Anal Bioanal Chem 389: 1549–1558

    PubMed  CAS  Google Scholar 

  213. Bovee TFH, Schoonen WGEJ, Hamers ARM, Bento MJ, Peijnenburg AACM (2008) Screening of synthetic and plant-derived compounds for (anti-)estrogenic and (anti-)androgenic activities. Anal Bioanal Chem 390: 1111–1119

    PubMed  CAS  Google Scholar 

  214. Richard S, Zingg HH (1990) The human oxytocin gene promoter is regulated by estrogens. J Biol Chem 265: 6098–6103

    PubMed  CAS  Google Scholar 

  215. Schippers IJ, Kloppenburg M, Waardenburg R, Ab G (1994) Cis-acting elements reinforcing the activity of the estrogen-response element in the very-low-density apolipoprotein II gene promoter. Eur J Biochem 221: 43–51

    PubMed  CAS  Google Scholar 

  216. Chang TC, Nardulli AM, Lew D, Shapiro DJ (1992) The role of estrogen response elements in expression of the Xenopus laevis vitellogenin B1 gene. Mol Endocrinol 6: 346–354

    PubMed  CAS  Google Scholar 

  217. Kastner P, Krust A, Turcotte B, Stropp U, Tora, L, Gronemeyer H, Chambon P (1990) Two distinct estrogen regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 9: 1603–1614

    PubMed  CAS  Google Scholar 

  218. Perlmann T, Eriksson P, Wrange ö (1990) Quantitative analysis of the glucocoticoid receptor-DNA interaction at the mouse mammary tumor virus glucocorticoid response element. J Biol Chem 265: 17222–17229

    PubMed  CAS  Google Scholar 

  219. Sun YN, DuBois DC, Almon RR, Pyszczynski NA, Jusko WJ (1998) Dose-dependent and repeatdose studies for receptor/gene-mediated pharmacodynamics of methylprednisolone on glucocorticoid receptor down-regulation and tyrosine aminotransferase induction in rat liver. J Pharmcokinet Biopharm 26: 619–648

    CAS  Google Scholar 

  220. Scott DK, Strömstedt PE, Wang JC, Granner DK (1998) Further characterisation of the glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene. The role of the glucocorticoid receptor-binding sites. Mol Endocrinol 12: 482–491

    PubMed  CAS  Google Scholar 

  221. Deckers GH, Schoonen WGEJ, Kloosterboer HJ (2000) Influence of the substitution of 11-methylene, Æ15, and/or 18-methyl groups in norethisterone on receptor binding, transactivation assays and biological activities in animals. J Steroid Biochem Mol Biol 72: 83–92

    Google Scholar 

  222. Soto AM, Maffini MV, Schaeberle CM, Sonnenschein C (2006) Strengths and weaknesses of in vitro assays for estrogenic and androgenic activity. Best Pract Res Clin Endocr Metab 20: 15–33

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, NV Organon (Schering- Plough), Oss, The Netherlands

    Willem G. E. J. Schoonen, Walter M. A. Westerink & G. Jean Horbach

Authors
  1. Willem G. E. J. Schoonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Walter M. A. Westerink
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Jean Horbach
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Federal Institute for Risk Assessment, Thielallee 88-92, 14195, Berlin, Germany

    Andreas Luch

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Birkhäuser Verlag/Switzerland

About this chapter

Cite this chapter

Schoonen, W.G.E.J., Westerink, W.M.A., Horbach, G.J. (2009). High-throughput screening for analysis of in vitro toxicity. In: Luch, A. (eds) Molecular, Clinical and Environmental Toxicology. Experientia Supplementum, vol 99. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8336-7_14

Download citation

Publish with us

Policies and ethics

Search

Navigation