A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity

Toxicology and Applied Pharmacology

Volumn 268, Issue 1, 2013, Pages 1-16

  Kostadinova, Radina ^a   Boess, Franziska ^a   Applegate, Dawn ^b   Suter, Laura ^a   Weiser, Thomas ^a   Singer, Thomas ^a   Naughton, Brian ^b   Roth, Adrian ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

^b Shire Regenerative Medicine   (United States)

Author keywords

Cytochrome P450; Drug safety assessment; Drug induced liver injury; Idiosyncratic toxicity; Predictive toxicology; Three dimensional liver co cultures

Indexed keywords

2,3,7,8 TETRACHLORODIBENZO PARA DIOXIN; ALBUMIN; ALPHA NAPHTHOFLAVONE; CYTOCHROME P450; DEXAMETHASONE; FENOFIBRATE; FIBRINOGEN; LEVOFLOXACIN; PARACETAMOL; PHENOBARBITAL; PIOGLITAZONE; RIFAMPICIN; SULFAPHENAZOLE; TRANSFERRIN; TROGLITAZONE; TROLEANDOMYCIN; TROVAFLOXACIN; UREA;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; COCULTURE; CONTROLLED STUDY; CYTOTOXICITY; ENDOTHELIUM CELL; ENZYME LINKED IMMUNOSORBENT ASSAY; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; INFLAMMATION; INTRAHEPATIC BILE DUCT; KUPFFER CELL; LIVER; LIVER CELL; LIVER CELL CULTURE; LIVER ENDOTHELIUM; LIVER FUNCTION; LIVER PARENCHYMA; LIVER TOXICITY; MALE; MONOLAYER CULTURE; NONHUMAN; PROTEIN SYNTHESIS; RAT; STELLATE CELL; THREE DIMENSIONAL LIVER COCULTURE SYSTEM; TOXIC HEPATITIS;

ADULT; ALBUMINS; ANIMALS; CELL SURVIVAL; COCULTURE TECHNIQUES; CYTOCHROME P-450 ENZYME SYSTEM; DRUG EVALUATION, PRECLINICAL; ENDOTHELIAL CELLS; ENZYME INHIBITORS; FIBRINOGEN; HEPATOCYTES; HUMANS; LIVER; MALE; MIDDLE AGED; RATS; RATS, WISTAR; TRANSFERRIN; UREA;

EID: 84873905748     PISSN: 0041008X     EISSN: 10960333     Source Type: Journal    
DOI: 10.1016/j.taap.2013.01.012     Document Type: Article

References (97)

1. Acharya S.S., Dimichele D.M. Rare inherited disorders of fibrinogen. Haemophilia 2008, 14:1151-1158.
2. Adams D.H., Ju C., Ramaiah S.K., Uetrecht J., Jaeschke H. Mechanisms of immune-mediated liver injury. Toxicol. Sci. 2010, 115:307-321.
3. Amacher D.E. The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury. Expert Opin. Drug Metab. Toxicol. 2012, 8:335-347.
4. Ansede J.H., Smith W.R., Perry C.H., St Claire R.L., Brouwer K.R. An in vitro assay to assess transporter-based cholestatic hepatotoxicity using sandwich-cultured rat hepatocytes. Drug Metab. Dispos. 2010, 38:276-280.
5. Ball P., Mandell L., Niki Y., Tillotson G. Comparative tolerability of the newer fluoroquinolone antibacterials. Drug Saf. 1999, 21:407-421.
6. Bates J., McClain C.J. The effect of severe zinc deficiency on serum levels of albumin, transferrin, and prealbumin in man. Am. J. Clin. Nutr. 1981, 34:1655-1660.
7. Begue J.M., Le Bigot J.F., Guguen-Guillouzo C., Kiechel J.R., Guillouzo A. Cultured human adult hepatocytes: a new model for drug metabolism studies. Biochem. Pharmacol. 1983, 32:1643-1646.
8. Bissell D.M., Arenson D.M., Maher J.J., Roll F.J. Support of cultured hepatocytes by a laminin-rich gel. Evidence for a functionally significant subendothelial matrix in normal rat liver. J. Clin. Invest. 1987, 79:801-812.
9. Bolton J.L., Trush M.A., Penning T.M., Dryhurst G., Monks T.J. Role of quinones in toxicology. Chem. Res. Toxicol. 2000, 13:135-160.
10. Brutman-Barazani T., Horovitz-Fried M., Aga-Mizrachi S., Brand C., Brodie C., Rosa J., Sampson S.R. Protein kinase Cdelta but not PKCalpha is involved in insulin-induced glucose metabolism in hepatocytes. J. Cell. Biochem. 2012, 113:2064-2076.
11. Cattley R.C., DeLuca J., Elcombe C., Fenner-Crisp P., Lake B.G., Marsman D.S., Pastoor T.A., Popp J.A., Robinson D.E., Schwetz B., Tugwood J., Wahli W. Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans?. Regul. Toxicol. Pharmacol. 1998, 27:47-60.
12. Chalasani N., Bjornsson E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology 2010, 138:2246-2259.
13. Cosgrove B.D., King B.M., Hasan M.A., Alexopoulos L.G., Farazi P.A., Hendriks B.S., Griffith L.G., Sorger P.K., Tidor B., Xu J.J., Lauffenburger D.A. Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. Toxicol. Appl. Pharmacol. 2009, 237:317-330.
14. Cosgrove B.D., Alexopoulos L.G., Hang T.C., Hendriks B.S., Sorger P.K., Griffith L.G., Lauffenburger D.A. Cytokine-associated drug toxicity in human hepatocytes is associated with signaling network dysregulation. Mol. Biosyst. 2010, 6:1195-1206.
15. Dash A., Inman W., Hoffmaster K., Sevidal S., Kelly J., Obach R.S., Griffith L.G., Tannenbaum S.R. Liver tissue engineering in the evaluation of drug safety. Expert Opin. Drug Metab. Toxicol. 2009, 5:1159-1174.
16. David S., Hamilton J.P. Drug-induced liver injury. US Gastroenterol. Hepatol. Rev. 2010, 6:73-80.
17. DeGorter M.K., Xia C.Q., Yang J.J., Kim R.B. Drug transporters in drug efficacy and toxicity. Annu. Rev. Pharmacol. Toxicol. 2012, 52:249-273.
18. Donato M.T., Jimenez N., Castell J.V., Gomez-Lechon M.J. Fluorescence-based assays for screening nine cytochrome P450 (P450) activities in intact cells expressing individual human P450 enzymes. Drug Metab. Dispos. 2004, 32:699-706.
19. Dunn J.C., Yarmush M.L., Koebe H.G., Tompkins R.G. Hepatocyte function and extracellular matrix geometry: long-term culture in a sandwich configuration. FASEB J. 1989, 3:174-177.
20. Escher P., Wahli W. Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat. Res. 2000, 448:121-138.
21. Gebhardt R., Hengstler J.G., Muller D., Glockner R., Buenning P., Laube B., Schmelzer E., Ullrich M., Utesch D., Hewitt N., Ringel M., Hilz B.R., Bader A., Langsch A., Koose T., Burger H.J., Maas J., Oesch F. 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, 35:145-213.
22. Ged C., Rouillon J.M., Pichard L., Combalbert J., Bressot N., Bories P., Michel H., Beaune P., Maurel P. The increase in urinary excretion of 6 beta-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. Br. J. Clin. Pharmacol. 1989, 28:373-387.
23. Gerlach J.C., Mutig K., Sauer I.M., Schrade P., Efimova E., Mieder T., Naumann G., Grunwald A., Pless G., Mas A., Bachmann S., Neuhaus P., Zeilinger K. Use of primary human liver cells originating from discarded grafts in a bioreactor for liver support therapy and the prospects of culturing adult liver stem cells in bioreactors: a morphologic study. Transplantation 2003, 76:781-786.
24. Griffith L.G., Swartz M.A. Capturing complex 3D tissue physiology in vitro. Nat. Rev. Mol. Cell Biol. 2006, 7:211-224.
25. Guguen-Guillouzo C., Guillouzo A. General review on in vitro hepatocyte models and their applications. Methods Mol. Biol. 2010, 640:1-40.
26. Guillouzo A. Liver cell models in in vitro toxicology. Environ. Health Perspect. 1998, 106(Suppl. 2):511-532.
27. Guo L., Zhang L., Sun Y., Muskhelishvili L., Blann E., Dial S., Shi L., Schroth G., Dragan Y.P. Differences in hepatotoxicity and gene expression profiles by anti-diabetic PPAR gamma agonists on rat primary hepatocytes and human HepG2 cells. Mol. Divers. 2006, 10:349-360.
28. Guo Y., Jolly R.A., Halstead B.W., Baker T.K., Stutz J.P., Huffman M., Calley J.N., West A., Gao H., Searfoss G.H., Li S., Irizarry A.R., Qian H.R., Stevens J.L., Ryan T.P. Underlying mechanisms of pharmacology and toxicity of a novel PPAR agonist revealed using rodent and canine hepatocytes. Toxicol. Sci. 2007, 96:294-309.
29. Hasmall S., James N., Hedley K., Olsen K., Roberts R. Mouse hepatocyte response to peroxisome proliferators: dependency on hepatic nonparenchymal cells and peroxisome proliferator activated receptor alpha (PPARalpha). Arch. Toxicol. 2001, 75:357-361.
30. Hewitt N.J., Lechon M.J., Houston J.B., Hallifax D., Brown H.S., Maurel P., Kenna J.G., Gustavsson L., Lohmann C., Skonberg C., Guillouzo A., Tuschl G., Li A.P., LeCluyse E., Groothuis G.M., Hengstler J.G. 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.
31. Hottelart C., El Esper N., Rose F., Achard J.M., Fournier A. Fenofibrate increases creatininemia by increasing metabolic production of creatinine. Nephron 2002, 92:536-541.
32. Iwaisako K., Haimerl M., Paik Y.H., Taura K., Kodama Y., Sirlin C., Yu E., Yu R.T., Downes M., Evans R.M., Brenner D.A., Schnabl B. Protection from liver fibrosis by a peroxisome proliferator-activated receptor delta agonist. Proc. Natl. Acad. Sci. U. S. A. 2012, 109:E1369-E1376.
33. James L.P., Mayeux P.R., Hinson J.A. Acetaminophen-induced hepatotoxicity. Drug Metab. Dispos. 2003, 31:1499-1506.
34. Kanebratt K.P., Diczfalusy U., Backstrom T., Sparve E., Bredberg E., Bottiger Y., Andersson T.B., Bertilsson L. Cytochrome P450 induction by rifampicin in healthy subjects: determination using the Karolinska cocktail and the endogenous CYP3A4 marker 4beta-hydroxycholesterol. Clin. Pharmacol. Ther. 2008, 84:589-594.
35. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat. Rev. Drug Discov. 2005, 4:489-499.
36. Khalil M., Shariat-Panahi A., Tootle R., Ryder T., McCloskey P., Roberts E., Hodgson H., Selden C. Human hepatocyte cell lines proliferating as cohesive spheroid colonies in alginate markedly upregulate both synthetic and detoxificatory liver function. J. Hepatol. 2001, 34:68-77.
37. Khetani S.R., Bhatia S.N. Microscale culture of human liver cells for drug development. Nat. Biotechnol. 2008, 26:120-126.
38. Kimoto E., Walsky R., Zhang H., Bi Y.A., Whalen K.M., Yang Y.S., Linder C., Xiao Y., Iseki K., Fenner K.S., El-Kattan A.F., Lai Y. Differential modulation of cytochrome P450 activity and the effect of 1-aminobenzotriazole on hepatic transport in sandwich-cultured human hepatocytes. Drug Metab. Dispos. 2012, 40:407-411.
39. Kirby B.J., Collier A.C., Kharasch E.D., Dixit V., Desai P., Whittington D., Thummel K.E., Unadkat J.D. Complex drug interactions of HIV protease inhibitors 2: in vivo induction and in vitro to in vivo correlation of induction of cytochrome P450 1A2, 2B6, and 2C9 by ritonavir or nelfinavir. Drug Metab. Dispos. 2011, 39:2329-2337.
40. Kostrubsky V.E., Sinclair J.F., Ramachandran V., Venkataramanan R., Wen Y.H., Kindt E., Galchev V., Rose K., Sinz M., Strom S.C. The role of conjugation in hepatotoxicity of troglitazone in human and porcine hepatocyte cultures. Drug Metab. Dispos. 2000, 28:1192-1197.
41. Kuri-Harcuch W., Mendoza-Figueroa T. Cultivation of adult rat hepatocytes on 3 T3 cells: expression of various liver differentiated functions. Differentiation 1989, 41:148-157.
42. Lauer B., Tuschl G., Kling M., Mueller S.O. Species-specific toxicity of diclofenac and troglitazone in primary human and rat hepatocytes. Chem. Biol. Interact. 2009, 179:17-24.
43. LeCluyse E.L. Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation. Eur. J. Pharm. Sci. 2001, 13:343-368.
44. LeCluyse E., Madan A., Hamilton G., Carroll K., DeHaan R., Parkinson A. Expression and regulation of cytochrome P450 enzymes in primary cultures of human hepatocytes. J. Biochem. Mol. Toxicol. 2000, 14:177-188.
45. Lecluyse E.L., Witek R.P., Andersen M.E., Powers M.J. Organotypic liver culture models: meeting current challenges in toxicity testing. Crit. Rev. Toxicol. 2012, 42:501-548.
46. Lee U.E., Friedman S.L. Mechanisms of hepatic fibrogenesis. Best Pract. Res. Clin. Gastroenterol. 2011, 25:195-206.
47. Lehmann J.M., McKee D.D., Watson M.A., Willson T.M., Moore J.T., Kliewer S.A. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 1998, 102:1016-1023.
48. Li J., Kaneko T., Wang Y., Qin L.Q., Wang P.Y., Sato A. Troglitazone enhances the hepatotoxicity of acetaminophen by inducing CYP3A in rats. Toxicology 2002, 176:91-100.
49. Li M.Y., Deng H., Zhao J.M., Dai D., Tan X.Y. PPARgamma pathway activation results in apoptosis and COX-2 inhibition in HepG2 cells. World J. Gastroenterol. 2003, 9:1220-1226.
50. Liu C., Tao Q., Sun M., Wu J.Z., Yang W., Jian P., Peng J., Hu Y., Liu P. Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats. Lab. Invest. 2010, 90:1805-1816.
51. Liu J., Abate W., Xu J., Corry D., Kaul B., Jackson S.K. Three-dimensional spheroid cultures of A549 and HepG2 cells exhibit different lipopolysaccharide (LPS) receptor expression and LPS-induced cytokine response compared with monolayer cultures. Innate Immun. 2011, 17:245-255.
52. Lloyd S., Hayden M.J., Sakai Y., Fackett A., Silber P.M., Hewitt N.J., Li A.P. Differential in vitro hepatotoxicity of troglitazone and rosiglitazone among cryopreserved human hepatocytes from 37 donors. Chem. Biol. Interact. 2002, 142:57-71.
53. Loi C.M., Young M., Randinitis E., Vassos A., Koup J.R. Clinical pharmacokinetics of troglitazone. Clin. Pharmacokinet. 1999, 37:91-104.
54. Lubberstedt M., Muller-Vieira U., Mayer M., Biemel K.M., Knospel F., Knobeloch D., Nussler A.K., Gerlach J.C., Zeilinger K. HepaRG human hepatic cell line utility as a surrogate for primary human hepatocytes in drug metabolism assessment in vitro. J. Pharmacol. Toxicol. Methods 2011, 63:59-68.
55. Madan A., Graham R.A., Carroll K.M., Mudra D.R., Burton L.A., Krueger L.A., Downey A.D., Czerwinski M., Forster J., Ribadeneira M.D., Gan L.S., LeCluyse E.L., Zech K., Robertson P., Koch P., Antonian L., Wagner G., Yu L., Parkinson A. Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metab. Dispos. 2003, 31:421-431.
56. Mari M., Colell A., Morales A., Caballero F., Moles A., Fernandez A., Terrones O., Basanez G., Antonsson B., Garcia-Ruiz C., Fernandez-Checa J.C. Mechanism of mitochondrial glutathione-dependent hepatocellular susceptibility to TNF despite NF-kappaB activation. Gastroenterology 2008, 134:1507-1520.
57. McGill M.R., Yan H.M., Ramachandran A., Murray G.J., Rollins D.E., Jaeschke H. HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity. Hepatology 2011, 53:974-982.
58. Michalopoulos G., Russell F., Biles C. Primary cultures of hepatocytes on human fibroblasts. In Vitro 1979, 15:796-806.
59. Mingoia R.T., Nabb D.L., Yang C.H., Han X. Primary culture of rat hepatocytes in 96-well plates: effects of extracellular matrix configuration on cytochrome P450 enzyme activity and inducibility, and its application in in vitro cytotoxicity screening. Toxicol. In Vitro 2007, 21:165-173.
60. Naughton B.A., Roman J.S., Sibanda B., Weintraub J.P., Kamali V. Stereotypic culture systems for liver and bone marrow: evidence for the development of functional tissue in vitro and following implantation in vivo. Biotechnol. Bioeng. 1994, 43:810-825.
61. Naughton B.A., Sibanda B., Weintraub J.P., San Roman J., Kamali V. A stereotypic, transplantable liver tissue-culture system. Appl. Biochem. Biotechnol. 1995, 54:65-91.
62. Nishimura J., Dewa Y., Okamura T., Muguruma M., Jin M., Saegusa Y., Umemura T., Mitsumori K. Possible involvement of oxidative stress in fenofibrate-induced hepatocarcinogenesis in rats. Arch. Toxicol. 2008, 82:641-654.
63. Nyfeler F., Fasel P., Walter P. Short-term stimulation of net glycogen production by insulin in rat hepatocytes. Biochim. Biophys. Acta 1981, 675:17-23.
64. O'Brien M.L., Spear B.T., Glauert H.P. Role of oxidative stress in peroxisome proliferator-mediated carcinogenesis. Crit. Rev. Toxicol. 2005, 35:61-88.
65. Ohta T., Masutomi N., Tsutsui N., Sakairi T., Mitchell M., Milburn M.V., Ryals J.A., Beebe K.D., Guo L. Untargeted metabolomic profiling as an evaluative tool of fenofibrate-induced toxicology in Fischer 344 male rats. Toxicol. Pathol. 2009, 37:521-535.
66. Pernelle K., Le Guevel R., Glaise D., Stasio C.G., Le Charpentier T., Bouaita B., Corlu A., Guguen-Guillouzo C. Automated detection of hepatotoxic compounds in human hepatocytes using HepaRG cells and image-based analysis of mitochondrial dysfunction with JC-1 dye. Toxicol. Appl. Pharmacol. 2011, 254:256-266.
67. Peters T.S. Do preclinical testing strategies help predict human hepatotoxic potentials?. Toxicol. Pathol. 2005, 33:146-154.
68. Peters J.M., Cheung C., Gonzalez F.J. Peroxisome proliferator-activated receptor-alpha and liver cancer: where do we stand?. J. Mol. Med. (Berl) 2005, 83:774-785.
69. Peterson T.C., Renton K.W. Depression of cytochrome P-450-dependent drug biotransformation in hepatocytes after the activation of the reticuloendothelial system by dextran sulfate. J. Pharmacol. Exp. Ther. 1984, 229:299-304.
70. Pradere J.P., Troeger J.S., Dapito D.H., Mencin A.A., Schwabe R.F. Toll-like receptor 4 and hepatic fibrogenesis. Semin. Liver Dis. 2010, 30:232-244.
71. Pritchard J.F., Jurima-Romet M., Reimer M.L., Mortimer E., Rolfe B., Cayen M.N. Making better drugs: decision gates in non-clinical drug development. Nat. Rev. Drug Discov. 2003, 2:542-553.
72. Roberts R.A., Ganey P.E., Ju C., Kamendulis L.M., Rusyn I., Klaunig J.E. Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol. Sci. 2007, 96:2-15.
73. Rost K.L., Brosicke H., Heinemeyer G., Roots I. Specific and dose-dependent enzyme induction by omeprazole in human beings. Hepatology 1994, 20:1204-1212.
74. Roth A., Boess F., Landes C., Steiner G., Freichel C., Plancher J.M., Raab S., de Vera Mudry C., Weiser T., Suter L. Gene expression-based in vivo and in vitro prediction of liver toxicity allows compound selection at an early stage of drug development. J. Biochem. Mol. Toxicol. 2011, 25:183-194.
75. Rudman D., DiFulco T.J., Galambos J.T., Smith R.B., Salam A.A., Warren W.D. Maximal rates of excretion and synthesis of urea in normal and cirrhotic subjects. J. Clin. Invest. 1973, 52:2241-2249.
76. Shaw P.J., Ganey P.E., Roth R.A. Tumor necrosis factor alpha is a proximal mediator of synergistic hepatotoxicity from trovafloxacin/lipopolysaccharide coexposure. J. Pharmacol. Exp. Ther. 2009, 328:62-68.
77. Shen C., Meng Q., Zhang G. Species-specific toxicity of troglitazone on rats and human by gel entrapped hepatocytes. Toxicol. Appl. Pharmacol. 2012, 258:19-25.
78. Sioud M., Melien O. Treatment options and individualized medicine. Methods Mol. Biol. 2007, 361:327-340.
79. Sivaraman A., Leach J.K., Townsend S., Iida T., Hogan B.J., Stolz D.B., Fry R., Samson L.D., Tannenbaum S.R., Griffith L.G. A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. Curr. Drug Metab. 2005, 6:569-591.
80. Smith M.T. Mechanisms of troglitazone hepatotoxicity. Chem. Res. Toxicol. 2003, 16:679-687.
81. Steiner G., Suter L., Boess F., Gasser R., de Vera M.C., Albertini S., Ruepp S. Discriminating different classes of toxicants by transcript profiling. Environ. Health Perspect. 2004, 112:1236-1248.
82. Sun Q., Zhu R., Foss F.W., Macdonald T.L. In vitro metabolism of a model cyclopropylamine to reactive intermediate: insights into trovafloxacin-induced hepatotoxicity. Chem. Res. Toxicol. 2008, 21:711-719.
83. Tacke F., Trautwein C., Yagmur E., Hellerbrand C., Wiest R., Brenner D.A., Schnabl B. Up-regulated eotaxin plasma levels in chronic liver disease patients indicate hepatic inflammation, advanced fibrosis and adverse clinical course. J. Gastroenterol. Hepatol. 2007, 22:1256-1264.
84. Tafazoli S., Spehar D.D., O'Brien P.J. Oxidative stress mediated idiosyncratic drug toxicity. Drug Metab. Rev. 2005, 37:311-325.
85. Toyoda Y., Tsuchida A., Iwami E., Miwa I. Toxic effect of troglitazone on cultured rat hepatocytes. Life Sci. 2001, 68:1867-1876.
86. Toyoda M., Takagi H., Horiguchi N., Kakizaki S., Sato K., Takayama H., Mori M. A ligand for peroxisome proliferator activated receptor gamma inhibits cell growth and induces apoptosis in human liver cancer cells. Gut 2002, 50:563-567.
87. Tukov F.F., Maddox J.F., Amacher D.E., Bobrowski W.F., Roth R.A., Ganey P.E. Modeling inflammation-drug interactions in vitro: a rat Kupffer cell-hepatocyte coculture system. Toxicol. In Vitro 2006, 20:1488-1499.
88. Tuschl G., Hrach J., Walter Y., Hewitt P.G., Mueller S.O. Serum-free collagen sandwich cultures of adult rat hepatocytes maintain liver-like properties long term: a valuable model for in vitro toxicity and drug-drug interaction studies. Chem. Biol. Interact. 2009, 181:124-137.
89. Vlase L., Popa A., Muntean D., Leucuta S.E. Pharmacokinetics and comparative bioavailability of two fenofibrate capsule formulations in healthy volunteers. Arzneimittelforschung 2010, 60:560-563.
90. 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, 31:1035-1042.
91. Wodicka L., Dong H., Mittmann M., Ho M.H., Lockhart D.J. Genome-wide expression monitoring in Saccharomyces cerevisiae. Nat. Biotechnol. 1997, 15:1359-1367.
92. Xu L., Li A.P., Kaminski D.L., Ruh M.F. 2,3,7,8 Tetrachlorodibenzo-p-dioxin induction of cytochrome P4501A in cultured rat and human hepatocytes. Chem. Biol. Interact. 2000, 124:173-189.
93. Yokoi T. Troglitazone. Handb. Exp. Pharmacol. 2010, 419-435.
94. Yuasa C., Tomita Y., Shono M., Ishimura K., Ichihara A. Importance of cell aggregation for expression of liver functions and regeneration demonstrated with primary cultured hepatocytes. J. Cell. Physiol. 1993, 156:522-530.
95. Zeilinger K., Schreiter T., Darnell M., Soderdahl T., Lubberstedt M., Dillner B., Knobeloch D., Nussler A.K., Gerlach J.C., Andersson T.B. Scaling down of a clinical three-dimensional perfusion multicompartment hollow fiber liver bioreactor developed for extracorporeal liver support to an analytical scale device useful for hepatic pharmacological in vitro studies. Tissue Eng. Part C Methods 2011, 17:549-556.
96. Zhang Y., Bachmeier C., Miller D.W. In vitro and in vivo models for assessing drug efflux transporter activity. Adv. Drug Deliv. Rev. 2003, 55:31-51.
97. Zhou Y.M., Wen Y.H., Kang X.Y., Qian H.H., Yang J.M., Yin Z.F. Troglitazone, a peroxisome proliferator-activated receptor gamma ligand, induces growth inhibition and apoptosis of HepG2 human liver cancer cells. World J. Gastroenterol. 2008, 14:2168-2173.