Comparisons between in vitro whole cell imaging and in vivo zebrafish-based approaches for identifying potential human hepatotoxicants earlier in pharmaceutical development

Drug Metabolism Reviews

Volumn 44, Issue 1, 2012, Pages 127-140

  Hill, Adrian ^a   Mesens, Natalie ^b   Steemans, Margino ^b   Xu, Jinghai James ^c   Aleo, Michael D ^d  

^a EVOTEC UK LTD   (United Kingdom)

^b JANSSEN RESEARCH FOUNDATION   (Belgium)

^c MERCK RESEARCH LABORATORIES   (United States)

^d PFIZER INC   (United States)

Author keywords

Danio rerio; hazard assessment; hepatotoxicity; high content screening; in vivo; Zebrafish

Indexed keywords

AMFEBUTAMONE; AMIODARONE; BREAST CANCER RESISTANCE PROTEIN; BUSPIRONE; CAPTOPRIL; CHLORPROMAZINE; CYCLOSPORIN; CYTOCHROME P450 2E1; DANAZOL; DANTROLENE; DEXAMETHASONE; DRUG METABOLIZING ENZYME; EPIDERMAL GROWTH FACTOR RECEPTOR 2; FELBAMATE; FENOFIBRATE; FLUTAMIDE; HEPATOTOXICANT; INDOMETACIN; LABETALOL; MERCAPTOPURINE; METHOTREXATE; MULTIDRUG RESISTANCE PROTEIN 1; MULTIDRUG RESISTANCE PROTEIN 2; NOMIFENSINE; STAVUDINE; SULINDAC; TAMOXIFEN; TETRACYCLINE; TOXIC SUBSTANCE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; CELL DAMAGE; CELL STRAIN HEPG2; CRYOPRESERVATION; DRUG DESIGN; DRUG INDUCED DISEASE; DRUG INDUSTRY; DRUG INFORMATION; DRUG LABELING; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG TRANSPORT; EMBRYO DEVELOPMENT; FLUORESCENCE MICROSCOPY; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL CULTURE; IMAGING; IN VITRO STUDY; IN VIVO STUDY; LARVA; LIVER CELL; MACHINE LEARNING; MAXIMUM PLASMA CONCENTRATION; MITOCHONDRIAL MEMBRANE POTENTIAL; NONHUMAN; PHENOTYPE; REVIEW; RISK ASSESSMENT; TOXIC HEPATITIS; TOXICITY TESTING; VALIDATION PROCESS; WHOLE CELL IMAGING; ZEBRA FISH;

ANIMALS; DRUG DESIGN; DRUG TOXICITY; DRUG-INDUCED LIVER INJURY; HUMANS; LIVER; MODELS, ANIMAL; PHARMACEUTICAL PREPARATIONS; REPRODUCIBILITY OF RESULTS; ZEBRAFISH;

EID: 84862937975     PISSN: 03602532     EISSN: 10979883     Source Type: Journal    
DOI: 10.3109/03602532.2011.645578     Document Type: Review

References (102)

1. Abboud, G., Kaplowitz, N. (2007). Drug-induced liver injury. Drug Saf 30:277-294. (Pubitemid 46624528)
2. Abraham, V. C., Towne, D. L., Waring, J. F., Warrior, U., Burns, D. J. (2008). Application of a high-content multiparameter cytotoxicity assay to prioritize compounds based on toxicity potential in humans. J Biomol Screen 13:527-537. (Pubitemid 351905075)
3. Alderton, W., Berghmans, S., Butler, P., Chassaing, H., Fleming, A., Golder, Z., et al. (2010). Accumulation and metabolism of drugs and CYP probe substrates in zebrafish larvae. Xenobiotica 40:547-557.
4. Aleo, M. D. (2009). Cellular imaging of hepatocytes to predict DILI. Recent research advances in drug-induced liver injury. Available at: http://www.aasld.org/conferences/educationtraining/Documents/ Hepatoxicity%20Slides/Aleo.pdf. Accessed on November 1, 2011.
5. Aleo, M. D., Doshna, C. M., Jones, M., Hill, A. (March 2010). Blinded assessment of hepatotoxic pharmaceuticals using zebrafish [Abstract #85]. The Toxicologist CD-an ofcial Journal of the Society of Toxicology, Volume 114.
6. Amacher, D. E. (2011). Strategies for the early detection of druginduced hepatic steatosis in preclinical drug safety evaluation studies. Toxicology 279:10-18.
7. Barros, T. P., Alderton, W. K., Reynolds, H. M., Roach, A. G., Berghmans, S. (2008). Zebrafish: an emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery. Br J Pharmacol 154:1400-1413.
8. Bauman, J. N., Kelly, J. M., Tripathy, S., Zhao, S. X., Lam, W. W., Kalgutkar, A. S., et al. (2009). Can in vitro metabolism-dependent covalent binding data distinguish hepatotoxic from nonhepatotoxic drugs? An analysis using human hepatocytes and liver S-9 fraction. Chem Res Toxicol 22:332-340.
9. Benbow, J. W., Aubrecht, J., Banker, M. J., Nettleton, D., Aleo, M. D. (2010). Predicting safety toleration of pharmaceutical chemical leads: cytotoxicity correlations to exploratory toxicity studies. Toxicol Lett 197:175-182.
10. Bi, Y.-A., Kazolias, D., Duignan, D. B. (2006). Use of cryopreserved human hepatocytes in sandwich culture to measure hepatobiliary transport. Drug Metab Dispos 34:1658-1665. (Pubitemid 44285409)
11. Boess, F., Kamber, M., Romer, S., Gasser, R., Muller, D., Albertini, S., et al. (2003). 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 73:386-402. (Pubitemid 36701742)
12. Bresolin, T., De Freitas Rebelo, M., Celso Dias Bainy, A. (2005). Expression of PXR, CYP3A, and MDR1 genes in liver of zebrafish. Comp Biochem Physiol C Toxicol Pharmacol 140, 403-407. (Pubitemid 40804361)
13. Carney, S. A., Peterson, R. E., Heideman, W. (2004). 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin activation of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator pathway causes developmental toxicity through a CYP1A-independent mechanism in zebrafish. Mol Pharmacol 66:512-521. (Pubitemid 39329249)
14. Chen, M., Vijay, V., Shi, Q., Liu, Z., Fang, H., Tong, W. (2011). FDA-approved drug labeling for the study of drug-induced liver injury. Drug Discov Today 16:697-703.
15. Cosgrove, B. D., Alexopoulos, L. G., Hang, T.-C., Hendriks, B. S., Sorger, P. K., Grifth, L. G., et al. (2010). Cytokine-associated drug toxicity in human hepatocytes is associated with signaling network dysregulation. Mol BioSyst 6:1195-1206.
16. Cosgrove, B. D., King, B. M., Hasan, M. A., Alexopoulos, L. G., Farazi, P. A., Hendriks, B. S., et al. (2009). Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. Toxicol Appl Pharmacol 237:317-330.
17. Daly, A. K. (2004). Pharmacogenetics of the cytochromes P450. Curr Top Med Chem 4:1733-1744. (Pubitemid 39654459)
18. Dimasi, J. A., Hansen, R. W., Grabowski, H. G. (2003). The price of innovation: new estimates of drug development costs. J Health Econ 22:151-185. (Pubitemid 36279392)
19. Dorne, J. L., Walton, K., Renwick, A. G. (2005). Human variability in xenobiotic metabolism and pathway-related uncertainty factors for chemical risk assessment: a review. Food Chem Toxicol 43:203-216. (Pubitemid 40037938)
20. Doshna, C., Benbow, J., Depasquale, M., Okerberg, C., Turnquist, S., Stedman, D., et al. (March 2009). Multi-phase analysis of uptake and toxicity in zebrafish: relationship to compound physicalchemical properties [Abstract #377]. The Toxicologist CD-an ofcial Journal of the Society of Toxicology, Volume 108.
21. Duncan, S. A. (2003). Mechanisms controlling early development of the liver. Mech Dev 120:19-33. (Pubitemid 35462093)
22. Eimon, P. M., Rubinstein, A. L. (2009). The use of in vivo zebrafish assays in drug toxicity screening. Expert Opin Drug Metab Toxicol 5:393-401.
23. Ekins, S., Williams, A. J., Xu, J. J. (2010). A predictive ligand-based Bayesian model for human drug-induced liver injury. Drug Metab Dispos 38:2302-2308.
24. Feng, B., Xu, J. J., Bi, Y. A., Mireles, R., Davidson, R., Duignan, D. B., et al. (2009). Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724, 714. Toxicol Sci 108:492-500.
25. Field, H. A., Ober, E. A., Roeser, T., Stainier, D. Y. (2003). Formation of the digestive system in zebrafish. I. Liver morphogenesis. Dev Biol 253:279-290. (Pubitemid 36259888)
26. Fung, M., Thornton, A., Mybeck, K., Hsiao-Hui, W., Hornbuckle, K., Muniz, E. (2001). Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceutical markets-1960 to 1999. Drug Inf J 35:293-317. (Pubitemid 32198581)
27. Goldstone, J. V., McArthur, A. G., Kubota, A., Zanette, J., Parente, T., Jonsson, M. E., et al. (2010). Identification and developmental expression of the full complement of cytochrome P450 genes in zebrafish. BMC Genomics 11:643.
28. Greaves, P., Williams, A., Eve, M. (2004). First dose of potential new medicines to humans: how animals help. Nat Rev Drug Discov 3:226-236. (Pubitemid 38379989)
29. Greene, N., Aleo, M. D., Louise-May, S., Price, D. A., Will, Y. (2010a). Using an in vitro cytotoxicity assay to aid in compound selection for in vivo safety studies. Bioorg Med Chem Lett 20:5308-5312.
30. Greene, N., Fisk, L., Naven, R. T., Note, R. R., Patel, M. L., Pelletier, D. J. (2010b). Developing structure-activity relationships for the prediction of hepatotoxicity. Chem Res Toxicol 23:1215-1222.
31. Gross-Steinmeyer, K., Stapleton, P. L., Tracy, J. H., Bammler, T. K., Lehman, T., Strom, S. C., et al. (2005). Influence of Matrigel-overlay on constitutive and inducible expression of nine genes encoding drug-metabolizing enzymes in primary human hepatocytes. Xenobiotica 35:419-438. (Pubitemid 41044388)
32. Hallare, A. V., Schirling, M., Luckenbach, T., Köhler, H. R., Triebskorn, R. (2005). Combined effects of temperature and cadmium on developmental parameters and biomarker responses in zebrafish (Danio rerio) embryos. J Therm Biol 30:7-17. (Pubitemid 39550400)
33. Hay, D. C., Pernagallo, S., Diaz-Mochon, J. J., Medine, C. N., Greenhough, S., Hannoun, Z., et al. (2011). Unbiased screening of polymer libraries to defne novel substrates for functional hepatocytes with inducible drug metabolism. Stem Cell Res 6:92-102.
34. Hewitt, N. J., Hewitt, P. (2004). Phase I and II enzyme characterization of two sources of HepG2 cell lines. Xenobiotica 34:243-256. (Pubitemid 38478893)
35. Hill, A. (2011). Hepatotoxicity testing in larval zebrafish. In: McGrath, P. (Ed.), Zebrafish: methods for assessing drug safety and toxicity. West Sussex, UK: Wiley-Balckwell.
36. Hill, A., Ball, J., Jones, M., Dodd, A., Mesens, N., Vanparys, P. (November 9-12, 2008). Implementation of zebrafish toxicity testing between in vitro and in vivo models to advance candidate selection [Abstract 08]. 29th Annual Meeting of the American College of Toxicology, Tucson, Arizona, USA, November 9-12, 2008.
37. Hill, A. J. (2008a). Zebrafish in drug discovery: bridging the gap between in vitro and in vivo methodologies. Preclinical World 121-123.
38. Hill AJ. (2008b). Zebrafish use in drug discovery [Abstract #977]. The Toxicologist CD-an ofcial Journal of the Society of Toxicology, Volume 102.
39. Hill, A. J., Howard, C. V., Cossins, A. R. (2002). Efcient embedding technique for preparing small specimens for stereological volume estimation: zebrafish larvae. J Microsc 206:179-181. (Pubitemid 34639414)
40. Hill, A. J., Teraoka, H., Heideman, W., Peterson, R. E. (2005). Zebrafish as a model vertebrate for investigating chemical toxicity. Toxicol Sci 86:6-19. (Pubitemid 41511344)
41. Hinton, D. E., Couch, J. A. (1998). Architectural pattern, tissue, and cellular morphology in livers of fishes: relationship to experimentally-induced neoplastic responses. EXS 86:141-164.
42. Hinton, D. E., Segner, H., Braunbeck, T. (2001). Toxic responses of the liver. In: Schlenk, D., Benson, W. H. (Eds.), Target organ toxicity in marine and freshwater teleosts: organs (pp. 248-298). London: Taylor and Francis.
43. Isogai, S., Horiguchi, M., Weinstein, B. M. (2001). The vascular anatomy of the developing zebrafish: an atlas of embryonic and early larval development. Dev Biol 230:278-301. (Pubitemid 32171423)
44. Ito, K., Chiba, K., Horikawa, M., Ishigami, M., Mizuno, N., Aoki, J., et al. (2002). Which concentration of the inhibitor should be used to predict in vivo drug interactions from in vitro data? AAPS PharmSci 4:E25.
45. Jani, J. P., Finn, R. S., Campbell, M., Coleman, K. G., Connell, R. D., Currier, N., et al. (2007). Discovery and pharmacologic characterization of CP-724, 714, a selective ErbB2 tyrosine kinase inhibitor. Cancer Res 67:9887-9893. (Pubitemid 47621237)
46. Jemnitz, K., Veres, Z., Vereczkey, L. (2010). Contribution of high basolateral bile salt efflux to the lack of hepatotoxicity in rat in response to drugs inducing cholestasis in human. Toxicol Sci 115:80-88.
47. Jones, D. P., Lemasters, J. J., Han, D., Boelsterli, U. A., Kaplowitz, N. (2010a). Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol Interv 10:98-111.
48. Jones, H. S., Panter, G. H., Hutchinson, T. H., Chipman, J. K. (2010b). Oxidative and conjugative xenobiotic metabolism in zebrafish larvae in vivo. Zebrafish 7:23-30.
49. Jones, M., Ball, J. S., Dodd, A., Hill, A. J. (2009). Comparison between zebrafish and Hep G2 assays for the predictive identification of hepatotoxins. Toxicology 262:13-14.
50. Kaplowitz, N. (2005). Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 4:489-499. (Pubitemid 40861991)
51. Kashimshetty, R, Desai, VG, Kale, VM, Lee, T, Moland, CL, Branham, WS, et al. (2009). Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity. Toxicol Appl Pharmacol 238:150-159.
52. Khetani, S. R., Bhatia, S. N. (2008). Microscale culture of human liver cells for drug development. Nat Biotechnol 26:120-126.
53. Kim, Y., Lasher, C. D., Milford, L. M., Murali, T. M., Rajagopalan, P. (2010). A comparative study of genome-wide transcriptional profiles of primary hepatocytes in collagen sandwich and monolayer cultures. Tissue Eng Part C Methods 16:1449-1460.
54. Knasmuller, S., Mersch-Sundermann, V., Kevekordes, S., Darroudi, F., Huber, W. W., Hoelzl, C., et al. (2004). Use of human-derived liver cell lines for the detection of environmental and dietary genotoxicants; current state of knowledge. Toxicology 198:315-328. (Pubitemid 38618063)
55. Lam, S. H., Mathavan, S., Tong, Y., Li, H., Karuturi, R. K. M., Wu, Y., et al. (2008). Zebrafish whole-adult-organism chemogenomics for large-scale predictive and discovery chemical biology. PLoS Genet 4:e1000121.
56. Lee, W. M. (2003). Drug-induced hepatotoxicity. N Engl J Med 349:474-485. (Pubitemid 36910027)
57. Lee, W. M., Senior, J. R. (2005). Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol 33:155-164. (Pubitemid 40216814)
58. Lee, Y. H., Chung, M. C., Lin, Q., Boelsterli, U. A. (2008). Troglitazoneinduced hepatic mitochondrial proteome expression dynamics in heterozygous Sod2 (+/-) mice: two-stage oxidative injury. Toxicol Appl Pharmacol 231:43-51.
59. Li, C., Seng, W. L., McGrath, P. (2008). Whole zebrafish cytochrome P450 microplate assays for assessing drug metabolism and drug safety [Abstract #777]. The Toxicologist CD-an ofcial Journal of the Society of Toxicology, Volume 102.
60. Li, N., Bi, Y.-A., Duignan, D. B., Lai, Y. (2009). Quantitative expression profile of hepatobiliary transporters in sandwich cultured rat and human hepatocytes. Mol Pharmaceut 6:1180-1189.
61. McGrath, P., Li, C.-Q. (2008). Zebrafish: a predictive model for assessing drug-induced toxicity. Drug Discov Today 13:394-401.
62. Mingoia, R. T., Nabb, D. L., Yang, C. H., Han, X. (2007). Primary culture of rat hepatocytes in 96-well plates: effects of extracellular matrix confguration on cytochrome P450 enzyme activity and inducibility, and its application in in vitro cytotoxicity screening. Toxicol In Vitro 21:165-173. (Pubitemid 44855523)
63. Morgan, R. E., Trauner, M., Van Staden, C. J., Lee, P. H., Ramachandran, B., Eschenberg, M., et al. (2010). Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci 118:485-500.
64. Munster, P. N., Britten, C. D., Mita, M., Gelmon, K., Minton, S. E., Moulder, S., et al. (2007). First study of the safety, tolerability, and pharmacokinetics of CP-724, 714 in patients with advanced malignant solid HER2-expressing tumors. Clin Cancer Res 13:1238-1245. (Pubitemid 46424065)
65. Navarro, V. J., Senior, J. R. (2006). Drug-related hepatotoxicity. N Engl J Med 354:731-739. (Pubitemid 43247143)
66. O'Brien, P., Haskins, J. R. (2007). In vitro cytotoxicity assessment. Methods Mol Biol 356:415-425.
67. O'Brien, P., Irwin, W., Diaz, D., Howard-Cofeld, E., Krejsa, C., Slaughter, M., et al. (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. (Pubitemid 44214526)
68. O'Brien, PJ, Slaughter, MR, Biagini, C, Diaz, D, Gao, B, Irwin, W, et al. (2003). Predicting drug-induced human hepatotoxicity with in vitro cytotoxicity assays. In: Proceedings Tox'03, London, UK, 2003.
69. Obach, R. S., Kalgutkar, A. S., Soglia, J. R., Zhao, S. X. (2008). Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. Chem Res Toxicol 21:1814-1822.
70. Ober, E. A., Field, H. A., Stainier, D. Y. (2003). From endoderm formation to liver and pancreas development in zebrafish. Mech Dev 120:5-18. (Pubitemid 35462092)
71. Olson, H., Betton, G., Robinson, D., Thomas, K., Monro, A., Kolaja, G., et al. (2000). Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32:56-67.
72. Ostapowicz, G., Fontana, R. J., Schiodt, F. V., Larson, A., Davern, T. J., Han, S. H., et al. (2002). Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 137:947-954. (Pubitemid 35440240)
73. Pack, M., Solnica-Krezel, L., Malicki, J., Neuhauss, S. C., Schier, A. F., Stemple, D. L., et al. (1996). Mutations affecting development of zebrafish digestive organs. Development 123:321-328. (Pubitemid 27056759)
74. Pardo-Martin, C., Chang, T.-Y., Koo, B. K., Gilleland, C. L., Wasserman, S. C. Yanik, M. F. (2010). High-throughput in vivo vertebrate screening. Nat Meth 7:634-636.
75. Peterson, R. T., Macrae, C. A. (2011). Systematic approaches to toxicology in the zebrafish. Annu Rev Pharmacol Toxicol Jan 17. [Epub ahead of print]
76. Pfeifer, A. M., Cole, K. E., Smoot, D. T., Weston, A., Groopman, J. D., Shields, P. G., et al. (1993). Simian virus 40 large tumor antigenimmortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. Proc Natl Acad Sci U S A 90:5123-5127. (Pubitemid 23182989)
77. Postlethwait, J. H., Woods, I. G., Ngo-Hazelett, P., Yan, Y. L., Kelly, P. D., Chu, F., et al. (2000). Zebrafish comparative genomics and the origins of vertebrate chromosomes. Genome Res 10:1890-1902. (Pubitemid 32049135)
78. Reuben, A. (2004). Hy's law. Hepatology 39:574-578.
79. Reuben, A., Koch, D. G., Lee, W. M. (2010). Drug-induced acute liver failure: results of a U. S. multicenter, prospective study. Hepatology 52:2065-2076.
80. Roth, R. A., Harkema, J. R., Pestka, J. P., Ganey, P. E. (1997). Is exposure to bacterial endotoxin a determinant of susceptibility to intoxication from xenobiotic agents? Toxicol Appl Pharmacol 147:300-311. (Pubitemid 28062747)
81. Routledge, P. A., O'Mahony, M. S., Woodhouse, K. W. (2004). Adverse drug reactions in elderly patients. Br J Clin Pharmacol 57:121-126. (Pubitemid 38223523)
82. Rubinstein, A. L. (2006). Zebrafish assays for drug toxicity screening. Expert Opin Drug Metab Toxicol 2:231-240. (Pubitemid 46372366)
83. Schoonen, W. G., Westerink, W. M., Horbach, G. J. (2009). Highthroughput screening for analysis of in vitro toxicity. EXS 99:401-452.
84. Selderslaghs, I. W., Blust, R., Witters, H. E. (2011). Feasibility study of the zebrafish assay as an alternative method to screen for developmental toxicity and embryotoxicity using a training set of 27 compounds. Reprod Toxicol Aug. 17. [Epub ahead of print]
85. Senior, J. R. (2007). Drug hepatotoxicity from a regulatory perspective. Clin Liver Dis 11:507-524. (Pubitemid 47304462)
86. Singh, Y. N. (2005). Potential for interaction of kava and St. John's wort with drugs. J Ethnopharmacol 100:108-113. (Pubitemid 41073531)
87. Stieger, B. (2010). Role of the bile salt export pump, BSEP, in acquired forms of cholestasis. Drug Metab Rev 42:437-445.
88. Stricker, B. H. C. (1992). Drug-induced hepatic injury. Amsterdam: Elsevier.
89. Swift, B., Pfeifer, N. D., Brouwer, K. L. (2010). Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity. Drug Metab Rev 42:446-471.
90. Taylor, D. L. (2010). A personal perspective on high-content screening (HCS): from the beginning. J Biomol Screen 15:720-725.
91. Temple, R. (2006). Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 15:241-243.
92. Tseng, H. P., Hseu, T. H., Buhler, D. R., Wang, W. D., Hu, C. H. (2005). Constitutive and xenobiotics-induced expression of a novel CYP3A gene from zebrafish larva. Toxicol Appl Pharmacol 205:247-258. (Pubitemid 40726300)
93. U. S., FDA. (2009). Guidance for industry-drug-induced liver injury: premarketing clinical evaluation. Available at: http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf. Accessed on November 1, 2011.
94. Uetrecht, J. (2007). Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol 47:513-539.
95. Van Den Bulck, K., Hill, A., Mesens, N., Diekman, H., De Schaepdrijver, L., Lammens, L. (2011). Zebrafish developmental toxicity assay: a fishy solution to reproductive toxicity screening, or just a red herring? Reprod Toxicol 32:213-219.
96. Walgren, J. L., Mitchell, M. D., Thompson, D. C. (2005). Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol 35:325-361. (Pubitemid 40691298)
97. Weigt, S., Huebler, N., Strecker, R., Braunbeck, T., Broschard, T. H. (2011). Zebrafish (Danio rerio) embryos as a model for testing proteratogens. Toxicology 281:25-36.
98. Wilkening, S., Bader, A. (2003). Influence of culture time on the expression of drug-metabolizing enzymes in primary human hepatocytes and hepatoma cell line HepG2. J Biochem Mol Toxicol 17:207-213. (Pubitemid 36974720)
99. Xu, J. J., Diaz, D., O'Brien, P. J. (2004). Applications of cytotoxicity assays and pre-lethal mechanistic assays for assessment of human hepatotoxicity potential. Chem Biol Interact 150:115-128. (Pubitemid 39441298)
100. Xu, J. J., Henstock, P. V., Dunn, M. C., Smith, A. R., Chabot, J. R., De Graaf, D. (2008). Cellular imaging predictions of clinical druginduced liver injury. Toxicol Sci 105:97-105.
101. Zhang, C, Willett, C., Fremgen, T. (2001). Zebrafish: an animal model for toxicological studies. New York: John Wiley & Sons, Inc.
102. Zimmerman, H. J. (1999). Drug-induced liver disease. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver, 2nd ed. (pp. 428-433) Philadelphia, Pennsylvania, USA: Lippincott Williams & Wilkins.