Evolving concepts in liver tissue modeling and implications for in vitro toxicology

Expert Opinion on Drug Metabolism and Toxicology

Volumn 4, Issue 10, 2008, Pages 1279-1294

  Guillouzo, André ^a   Guguen Guillouzo, Christiane ^a,b  

^a UNIVERSITÉ DE RENNES 1   (France)

^b PONTCHAILLOU UNIVERSITY HOSPITAL   (France)

Author keywords

HepaRG cells; Hepatoma cell lines; High throughput screening; Primary hepatocytes; Scaffolds; Stem cells; Toxicity testing; Toxicogenomics

Indexed keywords

CYTOCHROME P450 1A2;

ACCURACY; AMES TEST; CELL CULTURE; CELL DENSITY; CELL DIFFERENTIATION; CELL FUNCTION; CELL INTERACTION; CELL LINE; CELL STRAIN; CELL STRAIN HEPARG CELL; CELL SURVIVAL; CELL VIABILITY; COCULTURE; CULTURE MEDIUM; CYTOTOXICITY; ENZYME ACTIVITY; ENZYME INDUCTION; FATTY LIVER; GENETIC TOXICOLOGY; HUMAN; IN VITRO STUDY; INTEGRATED DISCRETE MULTIORGAN CELL CULTURE; LIVER CELL; LIVER CELL STORAGE; LIVER SLICE; LIVER TOXICITY; METHODOLOGY; MICROARRAY ANALYSIS; MODEL; NONHUMAN; REVIEW; STEM CELL; STORAGE; THICKNESS; TISSUE SLICE; TOXICITY TESTING;

ANIMALS; CELL CULTURE TECHNIQUES; CELL LINE; CELL LINE, TUMOR; HEPATOCYTES; HUMANS; LIVER; MODELS, BIOLOGICAL; PHENOTYPE; SIGNAL TRANSDUCTION; STEM CELLS; TOXICOGENETICS;

EID: 55049126741     PISSN: 17425255     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425255.4.10.1279     Document Type: Review

References (141)

1. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003;349:474-85
2. Lasser KE, Allen PD, Woolhandler SJ, et al. Tuning of new black box warnings and withdrawals for prescription medications. JAMA 2002;287:2215-20
3. Olson H, Betton G, Robinson D, et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 2000;32:56-67
4. Guillouzo A, Corlu A, Aninat C, et al. The human hepatoma heparg cells: a highly differentiated model for studies of liver metabolism and toxicity of xenobiotics. Chem Biol Interact 2007;168:66-73
5. Guillouzo A. Liver cell models in in vitro toxicology. Environ Health Perspect 1998;106(Suppl 2):511-32
6. De Graaf IAM, Groothuis GMM, Olinga P. Precision-cut tissue slices as a tool to predict metabolism of novel drugs. Expert Opin Drug Metab Toxicol 2007;3:879-98
7. Vickers AE, Fisher RL. Organ slices for the evaluation of human drug toxicity. Chem Biol Interact 2004;150:87-96
8. Jung D, Elferink MG, Stellaard F, Groothuis GM. Analysis of bile acid-induced regulation of FXR target genes in human liver slices. Liver Int 2007;27:137-44
9. Lerche-Langrand C, Toutain HJ. Precision-cut liver slices: characteristics and use for in vitro pharmaco-toxicology. Toxicology 2000;153:221-53
10. Toutain HJ, Moronvalle-Halley V, Sarsat JP, et al. Morphological and functional integrity of precision-cut rat liver slices in rotating organ culture and multiwell plate culture: effects of oxygen tension. Cell Biol Toxicol 1998;14:175-90
11. Schumacher K, Khong YM, Chang S, et al. Perfusion culture improves the maintenance of cultured liver tissue slices. Tissue Eng 2007;13:197-205
12. Fisher RL, Ulreich JB, Nakazato PZ, Brendel K. Histologycal and biochemical evaluation of precision cut liver slices. Toxicol Methods 2001;11:59-71
13. Fisher RL, Hasal SJ, Sanuik JT, et al. Cold and cryopreservation of dog liver and kidney slices. Cryobiology 1996;33:163-71
14. De Graaf IA, Draaisma AL, Schoeman O, et al. Cryopreservation of rat precision-cut liver and kidney slices by rapid freezing and vitrification. Cryobiology 2007;54:1-12
15. Guguen-Guillouzo C, Guillouzo. A Modulation of functional activities in cultured rat hepatocytes. Mol Cell Biochem 1983;53-54:35-56
16. Abdel-Razzak Z, Loyer P, Fautrel A, et al. Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. Mol Pharmacol 1993;44:707-15
17. Chesne C, Guyomard C, Guillouzo A, et al. Metabolism of meloxicam in human liver involves cytochromes P4502C9 and 3A4. Xenobiotica 1998;28:1-13
18. Guillouzo A, Morel F, Ratanasavanh D, et al. Long-term culture of functional hepatocytes. Toxicol In Vitro 1990;4:415-27
19. Hewitt NJ, Lechón MJ, Houston JB, et al. Primary hepatocytes: current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab Rev 2007;39:159-234
20. Gebhardt R, Hengsder JG, Müller D, et al. New hepatocyte in vitro systems for drug metabolism: metabolic capacity and recommendations for application in basic research and drug development, standard operation procedures. Drug Metab Rev 2003;5:145-213
21. Enat R, Jefferson DM, Ruiz-Opazo N, et al. Hepatocyte proliferation in vitro: its dependence on the use of serum-free hormonally defined medium and substrata of extracellular matrix. Proc Natl Acad Sci USA 1984;81:1411-5
22. Isom HC, Secott T, Georgoff I, et al. Maintenance of differentiated rat hepatocytes in primary culture. Proc Natl Acad Sci USA 1985;82:3252-6
23. Lanford RE, Carey KD, Estlack LE, et al. Analysis of plasma protein and lipoprotein synthesis in long-term primary cultures of baboon hepatocytes maintained in serum-free medium. In Vitro Cell Dev Biol 1989;25:174-82
24. Ferrini JB, Pichard L, Domergue J, Maurel P. Long-term primary cultures of adult human hepatocytes. Chem Biol Interact 1997;107:31-45
25. Meneses-Lorente G, Pattison C, Guyomard C, et al. Utility of long-term cultured human hepatocytes as an in vitro model for cytochrome P450 induction. Drug Metab Dispos 2007;5:215-20
26. Bissell DM, Arenson DM, Maher JJ, Roll FJ. Support of cultured hepatocytes by a laminin-rich gel evidence for a functionally significant subendothelial matrix in normal rat liver. J Clin Invest 1987;79:801-12
27. Dunn JC, Yarmush ML, Koebe HG, Tompkins RG. Hepatocyte function and extracellular matrix geometry: long-term culture in a sandwich configuration. FASEB J 1989;3:174-7
28. Lecluyse EL. Human hepatocyte culture systems for the in vitro evaluation of cyrochrome P450 expression and regulation. Eur J Pharm Sci 2001;13:343-68
29. Guguen-Guillouzo C. Role of homotypic and heterotypic cell interactions in expression of specific functions by cultured hepatocytes. In: Guillouzo A, Guguen-Guillouzo C, editors, Isolated and cultuted hepatocytes. John Libbey Eurotext-Inserm, Paris; 1986. p. 259-83
30. Guguen-Guillouzo C, Clément B, Baffet G, et al. Maintenance and reversibility of active albumin secretion by adult rat hepatocytes co-cultured with another liver epithelial cell type. Exp Cell Res 1983;143:47-54
31. Clement B, Guguen-Guillouzo C, Campion JP, et al. Long-term co-cultures of adult human hepatocytes with rat liver epithelial cells: modulation of albumin secretion and accumulation of extracellular material. Hepatology 1984;4:373-80
32. Guillouzo A, Beaune P, Gascoin MN, et al. Maintenance of cytochrome P-450 in cultured adult human hepatocytes. Biochem Pharmacol 1985;34:2991-5
33. Foliot A, Glaise D, Ettinger S, Guguen-Guillouzo C. Long-term maintenance of taurocholate uptake by adult rat hepatocytes co-cultured with a liver epithelial cell line. Hepatology 1985;5:215-9
34. Fraslin JM, Kneip B, Vaulont S, et al. Dependence of hepatocyte-specific gene expression on cell-cell interactions in primary culture. EMBO J 1985;4:2487-91
35. Corlu A, Kneip B, Lhadi C, et al. A plasma membrane protein is involved in cell contact-mediated regulation of tissue-specific genes in adult hepatocytes. J Cell Biol 1991;115:505-15
36. Goulet F, Normand C, Morin O. Cellular interactions promote tissue-specific function, biomatrix deposition and junctional communication of primary cultured hepatocytes. Hepatology 1988;8:1010-8
37. Khetani SR, Bhatia SN. Microscale culture of human liver cells for drug development. Nat Biotechnol 2008;26:120-6
38. Koide N, Sakaguchi K, Koide Y, et al. Formation of multicellular spheroids composed of adult rat hepatocytes in dishes with positively charged surfaces and under other nonadherent environments. Exp Cell Res 1990;186:227-35
39. Bhandari RN, Riccalton LA, Lewis AI, et al. Liver tissue engineering: a role for co-culture systems in modifying hepatocyte function and viability. Tissue Eng 2001;7:345-57
40. Riccalton-Banks L, Liew C, Bhandari R, et al. Long-term culture of functional liver tissue: three-dimensional coculture of primary hepatocytes and stellate cells. Tissue Eng 2003;9:401-10
41. Allen JW, Hassanein T, Bhatia SN. Advances in bioartificial liver devices. Hepatology 2001;34:447-55
42. Orive G, Gascón AR, Hernández RM, et al. Techniques: new approaches to the delivery of biopharmaceuticals. Trends Pharmacol Sci 2004;25:382-7
43. Fremond B, Malandain C, Guyomard C, et al. Correction of bilirubin conjugation in the gunn rat using hepatocytes immobilized in alginate gel beads as an extracorporeal bioartificial liver. Cell Transplant 1993;2:453-60
44. Guyomard C, Rialland L, Fremond B, et al. Influence of alginate gel entrapment and cryopreservation on survival and xenobiotic metabolism capacity of rat hepatocytes. Toxicol Appl Pharmacol 1996;141:349-56
45. Allen JW, Khetani SR, Bhatia SN. In vitro zonation and toxicity in a hepatocyte bioreactor. Toxicol Sci 2005;84:110-9
46. Hammond JS, Beckingham IJ, Shakesheff KM. Scaffolds for liver tissue engineering. Expert Rev Med Devices 2006;3:21-7
47. Coecke S, Ahr H, Blaauboer BJ, et al. Metabolism: a bottleneck in in vitro toxicological test development The report and recommendations of ecvam workshop 54. Altern Lab Anim 2006;34:49-84
48. Gómez-Lechón MJ, Donato MT, Castell JV, Jover R. Human hepatocytes in primary culture: the choice to investigate drug metabolism in man. Curr Drug Metab 2004;5:443-62
49. Morel F, Beaune PH, Ratanasavanh D, et al. Expression of cytochrome P-450 enzymes in cultured human hepatocytes. Eur J Biochem 1990;191:437-44
50. Madan A, Graham RA, Carroll KM, et al. Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos 2003;31:421-31
51. Diaz D, Fabre I, Daujat M, et al. Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. Gastroenterology 1990;99:737-47
52. Loyer P, Cariou S, Glaise D, et al. Growth factor dependence of progression through g1 and s phases of adult rat hepatocytes in vitro. Evidence of a mitogen restriction point in mid-late G1. J Biol Chem 1996;271:11484-92
53. Edwards AM, Michalopoulos GK. Conditions for frowth of hepatocytes in culture. In: Berry MN, Edwards AM, editors, The hepatocyte review. Kluwer Academic Publishers, Dordrecht; 2000. p. 73-96
54. Serandour AL, Loyer P, Garnier D, et al. Tnfalpha-mediated extracellular matrix remodeling is required for multiple division cycles in rat hepatocytes. Hepatology 2005;41:478-86
55. Poullain MG, Fautrel A, Guyomard C, et al. Viability and primary culture of rat hepatocyres after hypothermic preservation: the superiority of the leibovitz medium over the university of wisconsin solution for cold storage. Hepatology 1992;15:97-106
56. Guillouzo A, Guyomard C, Fautrel A, Chesne C. Storage of isolated hepatocytes. In: Berry MN, Edwards AM, editors, The hepatocyte review. Kluwer Academic Publishers, Dordrecht; 2000. p. 125-45
57. Chesné C, Guyomard C, Fautrel A, et al. Viability and function in primary culture of adult hepatocytes from various animal species and human beings after cryopreservation. Hepatology 1993;18:406-14
58. Utesch D, Diener B, Molitor E, et al. Characterization of cryopreserved rat liver parenchymal cells by metabolism of diagnostic substrates and activities of related enzymes. Biochem Pharmacol 1992;44:309-15
59. Guyomard C, Rialland L, Fremond B, et al. influence of alginate gel entrapment and cryopreservation on survival and xenobiotic metabolism capacity of rat hepatocytes. Toxicol Appl Pharmacol 1996;141:349-56
60. Fautrel A, Joly B, Guyomard C, Guillouzo A. Long-term maintenance of drug-metabolizing Enzyme activities in rat Hepatocytes after cryopreservation. Toxicol Appl Pharmacol 1997;147:110-4
61. Wu Y, Yu H, Chang S, et al. Vitreous cryopreservation of cell-biomaterial constructs involving encapsulated hepatocytes. Tissue Eng 2007;13:649-58
62. Rialland L, Guyomard C, Scotte M, et al. Viability and drug metabolism capacity of alginate-entrapped hepatocytes after cryopreservation. Cell Biol Toxicol 2000;6:105-16
63. Mahler S, Desille M, Frémond B, et al. Hypothermic storage and cryopreservation of hepatocytes: the protective effect of alginate gel against cell damages. Cell Transplant 2003;12:579-92
64. Moshage HJ, Rijntjes PJ, Hafkenscheid JC, et al. Primary culture of cryopreserved adult human hepatocytes on homologous extracellular matrix and the influence of monocytic products on albumin synthesis. J Hepatol 1988;7:34-44
65. The FDA. Available from: www.fda.gov/cder/guidance/6695dft.pdf
66. McGinnity DF, Soars MG, Urbanowicz RA, Riley RJ. Evaluation of fresh and cryopreserved hepatocytes as in vitro drug metabolism tools for the prediction of metabolic clearance. Drug Metab Dispos 2004;32:1247-53
67. Brown HS, Griffin M, Houston JB. Evaluation of cryopreserved human hepatocytes as an alternative in vitro system to microsomes for the prediction of metabolic clearance. Drug Metab Dispos 2007;35:293-301
68. Pfeifer AM, Cole KE, Smoot DT, et al. Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. Proc Natl Acad Sci USA 1993;90:5123-7
69. Castell JV, Jover R, Martínez-Jiménez CP, Gómez-Lechón MJ. Hepatocyte cell lines: their use, scope and limitations in drug metabolism studies. Expert Opin Drug Metab Toxicol 2006;2:183-212
70. Mills JB, Rose KA, Sadagopan N, et al. Induction of drug Metabolism enzymes and MDR1 using a novel human hepatocyte cell line. J Pharmacol Exp Ther 2004;309:303-9
71. Hariparsad N, Carr BA, Evers R, Chu X. Comparison of immortalized FA2N-4 cells and human hepatocytes as in vitro models for cytochrome P450 induction. Drug Metab Dispos 2008;36:1046-55
72. Le Jossic C, Glaise D, Corcos L, et al. Trans-acting factors, detoxication enzymes and hepatitis B virus replication in a novel set of human hepatoma cell lines. Eur J Biochem 1996;238:400-9
73. Ogino M, Nagata K, Yamazoe Y. Selective suppressions of human CYP3A forms, CYP3A5 and CYP3A7, by troglitazone in Hepg2 cells. Drug Metab Pharmacokinet 2002;17:42-6
74. Wilkening S, Stahl F, Bader A. Comparison of primary human hepatocytes and hepatoma cell line Hepg2 with regard to their biotransformation properties. Drug Metab Dispos 2003;31:1035-42
75. Majer BJ, Mersch-Sundermann V, Darrouch F, et al. Genotoxic effects of dietary and lifestyle related carcinogens in human derived hepatoma (Hepg2, Hep3b) cells. Mutat Res 2004;551:153-66
76. Gómez-Lechón MJ, Donato T, Jover R, et al. Expression and induction of a large set of drug-metabolizing enzymes by the highly differentiated human hepatoma cell line Bc2. Eur J Biochem 2001;268:1448-59
77. Hewitt NJ, Hewitt P. Phase I and II enzyme characterization of two sources of Hepg2 cell lines. Xenobiotica 2004;34:243-56
78. Kobayashi K, Sueyoshi T, Inoue K, et al. Cytoplasmic accumulation of the nuclear receptor car by a tetratricopeptide repeat protein in Hepg2 cells. Mol Pharmacol 2003;64:1069-75
79. Sueyoshi T, Kawamoto T, Zelko I, et al. The repressed nuclear receptor car responds to phenobarbital in activating the human CYP2B6 gene. J Biol Chem 1999;274:6043-6
80. Persson KP, Ekehed S, Otter C, et al. Evaluation of human liver slices and reporter gene assays as systems for predicting the cytochrome P450 induction potential of drugs in vivo in humans. Pharm Res 2006;23:56-69
81. Gripon P, Rumin S, Urban S, et al. Infection of a human hepatoma cell line by hepatitis B virus. Proc Natl Acad Sci USA 2002;99:15655-60
82. Cerec V, Glaise D, Garnier D, et al. Transdifferentiation of hepatocyte-like cells from the human hepatoma heparg cell line through bipotent progenitor. Hepatology 2007;45:957-67
83. Aninat C, Piton A, Glaise D, et al. Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma heparg cells. Drug Metab Dispos 2006;34:75-83
84. Le Vee M, Jigorel E, Glaise D, et al. Functional expression of sinusoidal and canalicular hepatic drug transporters in the differentiated human hepatoma heparg cell line. Eur J Pharm Sci 2006;28:109-17
85. Josse R, Aninat C, Glaise D, et al. Long-term functional stability of human heparg hepatocytes and use for chronic toxicity and genotoxicity studies. Drug Metab Dispos 2008;36:1111-8
86. Aninat C, Seguin P, Descheemaeker P, et al. Catecholamines induce an inflammatory response in human hepatocytes. Crit Care Med 2008;36:848-54
87. Kanebratt KP, Andersson TB. Heparg cells as an in vitro model for evaluation of cytochrome P450 induction in humans. Drug Metab Dispos 2008;36:137-45
88. Davila JC, Cezar GG, Thiede M, et al. Use and application of stem cells in toxicology. Toxicol Sci 2004;79:214-23
89. Wang HS, Hung SC, Peng ST, et al. Mesenchymal stem cells in the wharton's jelly of the human umbilical cord. Stem Cells 2004;22:1330-7
90. Karahuseyinoglu S, Cinar O, Kilic E, et al. Biology of stem cells in human umbilical cord stroma: in situ and in vitro surveys. Stem Cells 2003;25:319-31
91. Campard D, Lysy PA, Najimi M, Sokal EM. Native umbilical cord matrix stem cells express hepatic markers and differentiate into hepatocyte-like cells. Gastroenterology 2008;134:833-48
92. Duret C, Gerbal-Chaloin S, Ramos J, et al. Isolation, characterization, and differentiation to hepatocyte-like cells of nonparenchymal epithelial cells from adult human liver. Stem Cells 2007;25:1779-90
93. Schmelzer E, Zhang L, Bruce A, et al. Human hepatic stem cells from fetal and postnatal donors. J Exp Med 2007;204:1973-87
94. Herrera MB, Bruno S, Buttiglieri S, et al. Isolation and characterization of a stem cell population from adult human liver. Stem Cells 2006;24:2840-50
95. Schwartz RE, Reyes M, Koodie L, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 2002;109:1291-302
96. Snykers S, Vanhaecke T, Papeleu P, et al. Sequential exposure to cytokines reflecting embryogenesis: the key for in vitro differentiation of adult bone marrow stem cells into Functional hepatocyte-like cells. Toxicol Sci 2006;94:330-41
97. Jiang Y, Henderson D, Blackstad M, et al. Nearoectodermal differentiation from mouse multipotent adult progenitor cells. Proc Natl Acad Sci USA 2003;100:11854-60
98. Gouon-Evans V, Boussemart L, Gadue P, et al. BMP4 iS required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol 2006;24:1402-11
99. Hay DC, Zhao D, Ross A, et al. Direct differentiation of human embryonic stem cells to hepatocyte-like cells exhibiting functional activities. Cloning Stem Cells 2007;9:51-62
100. Hengstler JG, Brulport M, Schormann W, et al. Generation of human hepatocytes by stem cell technology: definition of the hepatocyte. Expert Opin Drug Metab Toxicol 2005;1:61-74
101. Ek M, Söderdahl T, Küppers-Munther B, et al. Expression of drug metabolizing enzymes in hepatocyte-like cells derived hom human embryonic stem cells. Biochem Pharmacol 2007;74:496-503
102. Lysy PA, Campard D, Smets F, et al. Persistence of a chimerical phenotype after hepatocyte differentiation of human bone marrow mesenchymal stem cells. Cell Prolif 2008;41:6-58
103. Mannello F, Tonti GA. Concise review: no breakthroughs for human mesenchymal and embryonic stem cell culture: conditioned medium, feeder layer, or feeder-free; medium with fetal calf serum, human serum, or enriched plasma; serum-free, serum replacement nonconditioned medium, or ad hoc formula? All that glitters is not gold! Stem Cells 2007;25:1603-9
104. Brulport M, Schormann W, Bauer A, et al. Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers. Hepatology 2007;46:861-70
105. Ratanasavanh D, Beaune P, Morel F, et al. Intralobular distribution and quantication of cytochrome P-450 enzymes in human liver as a function of age. Hepatology 1991;13:1142-51
106. Amin K, Ip C, Sato B, et al. Characterization of anit-induced toxicity using precision-cut rat and dog liver slices cultured in a dynamic organ roller system. Toxicol Pathol 2006;34:776-84
107. Fautrel A, Chesne C, Guillouzo A, et al. A multicentre study of acute in vitro cytotoxicity in rat hepatocytes: tentative correlation between in vitro toxicities and in vivo data. Altern Lab Anim 1993;21:281-4
108. De Gottardi A, Vinciguerra M, Sgroi A, et al. Microarray analyses and molecular profiling of steatosis induction in immortalized human hepatocytes. Lab Invest 2007;87:792-806
109. Gómez-Lechón MJ, Donato MT, Martínez-Romero A, et al. A human hepatocellular in vitro model to investigate steatosis. Chem Biol Interact 2007;165:106-16
110. Kenne K, Skanberg I, Glinghammar B, et al. Prediction of drug-induced liver injury in humans by using in vitro methods: the case of ximelagatran. Toxicol In Vitro 2008;22:730-46
111. Ratanasavanh D, Baffet G, Latinier MF, et al. Use of hepatocyte co-cultures in the assessment of drug toxicity from chronic exposure. Xenobiotica 1988;18:765-71
112. Kirkland DJ, Henderson L, Marzin D, et al. Testing strategies in mutagenicity and genetic toxicology: an appraisal of the guidelines of the european scientific committee for cosmetics and non-food products for the evaluation of hair dyes. Mutat Res 2005;588:88-105
113. Suter W. Predictive value of in vitro safety studies. Curr Opin Chem Biol 2006;10:362-6
114. Brambilla G, Martelli A. Failure of the standard battery of short-term tests in detecting some rodent and human genotoxic carcinogens. Toxicology 2004;196:1-19
115. Baudoin R, Corlu A, Griscom L, et al. Trends in the development of microfluidic cell biochips for in vitro hepatotoxicity. Toxicol In Vitro 2007;21:535-54
116. Lemaire F, Mandon CA, Reboud J, et al. Toxicity assays in nanodrops combining bioassay and morphometric endpoints. PLoS One 2007;2:E163
117. Abberger T, Jennings P, Mirlach A, et al. Application of a population balance model to a perfusion in vitro toxicity system. Toxicol In Vitro 2006;20:1213-24
118. Miret S, De Groene EM, Klaffke W. Comparison of in vitro assays of cellular toxicity in the human hepatic cell hne Hepg2. J Biomol Screen 2006;11:184-9
119. Dambach DM, Andrews BA, Moulin F. New technologies and screening strategies for hepatotoxicity: use of in vitro models. Toxicol Pathol 2005;33:17-26
120. O'Brien PJ, Siraki AG. Accelerated cytotoxicity mechanism screening using drug metabolising enzyme modulators. Curr Drug Metab 2005;6:101-9
121. Li AP, Bode C, Sakai Y. A novel in vitro system, the integrated discrete multiple organ cell culture (IDMOC) system, for the evaluation of human drug toxicity: comparative cytotoxicity of tamoxifen towards normal human cells from five major organs and MCF-7 adenocarcinoma breast cancer cells. Chem Biol Interact 2004;150:129-36
122. Lee MY, Park CB, Dordick JS, Clark DS. Metabolizing enzyme toxicology assay chip (METACHIP) for high-throughput microscale toxicity analyses. Proc Natl Acad Sci USA 2005;102:83-7
123. Liguori MJ, Anderson MG, Bukofzer S, et al. Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin. Hepatology 2005;41:177-86
124. Olsavsky KM, Page JL, Johnson MC, et al. Gene expression profiling and differentiation assessment in primary human hepatocyte cultures, established hepatoma cell lines, and human liver tissues. Toxicol Appl Pharmacol 2007;222:42-56
125. Elferink MG, Olinga P, Draaisma AL, et al. Microarray analysis in rat liver slices correctly predicts in vivo hepatotoxicity. Toxicol Appl Pharmacol 2008;229:300-9
126. Suzuki H, Inoue T, Matsushita T, et al. In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes. J Appl Toxicol 2008;28:227-36
127. Boess F, Kamber M, Romer S, et al. Gene expression in two hepatic cell lines, cultured primary hepatocytes, and liver slices compared to the in vivo liver gene expression in rats: possible implications for toxicogenomics use of in vitro systems. Toxicol Sci 2003;73:386-402
128. Mcmillian M, Nie AY, Parker JB, et al. A gene expression signature for oxidant stress/reactive metabofites in rat liver. Biochem Pharmacol 2004;68:2249-61
129. Reymann S, Borlak J. Transcriptome profiling of human hepatocytes treated with aroclor 1254 reveals transcription factor regulatory networks and clusters of regulated genes. BMC Genomics 2006;7:217
130. Van Delft JH, Van Agen E, Van Breda SG, et al. Comparison of supervised clustering methods to discriminate genotoxic from non-genotoxic carcinogens by gene expression profiling. Mutat Res 2005;575:17-33
131. Beekman JM, Boess F, Hildebrand H, et al. Gene expression analysis of the hepatotoxicant methapyrilene in primary rat hepatocytes: an interlaboratory study. Environ Health Perspect 2006;114:92-99
132. Waring JF, Ciurlionis R, Jolly RA, et al. Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity. Toxicol Lett 2001;20:359-68
133. Lambert C, Spire C, Renaud MP, et al. Effects of phenobarbital overdosage on gene expression in human HepaRg cells [abstract]. International Congress of Toxicology 2007; Mortural
134. Waters NJ, Holmes E, Waterfield CJ, et al. NMR and pattern recognition studies on liver extracts and intact livers from rats treated with alpha-naphthylisothiocyanate. Biochem Pharmacol 2002;64:67-77
135. Snyder RD, Green JW. A review of the genotoxicity of marketed pharmaceuticals. Mutat Res 2001;488:151-69
136. Fielden MR, Nie A, McMillian M, et al. Predictive safety testing consortium; carcinogenicity working group Interlaboratory evaluation of genomic signatures for predicting carcinogenicity in the rat. Toxicol Sci 2008;103:28-34
137. Fielden MR, Brennan R, Gollub J. A gene expression biomarker provides early prediction and mechanistic assessment of hepatic tumor induction by nongenotoxic chemicals. Toxicol Sci 2007;99:90-100
138. Nie AY, McMillian M, Parker JB, et al. Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicity. Mol Carcinog 2006;45:914-33
139. Ellinger-Ziegelbauer H, Gmuender H, Bandenburg A, Ahr HJ. Prediction of a carcinogenic potential of rat hepatocarcinogens using toxicogenomics analysis of short-term in vivo studies. Mutat Res 2008;637:23-39
140. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131:861-72
141. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007;31:1917-20