• 1
    Olsen AK, Whalen MD. Public perceptions of the pharmaceutical industry and drug safety: implications for the pharmacovigilance professional and the culture of safety. Drug Saf 2009; 32: 805810.
  • 2
    Davies EC, Green CF, Mottram DR, Rowe PH, Pirmohamed M. Emergency re-admissions to hospital due to adverse drug reactions within 1 year of the index admission. Br J Clin Pharmacol 2010; 70: 749755.
  • 3
    Davies EC, Green CF, Taylor S, Williamson PR, Mottram DR, Pirmohamed M. Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes. PLoS ONE 2009; 4: e4439.
  • 4
    Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 2004; 329: 1519.
  • 5
    Antoine DJ, Williams DP, Park BK. Understanding the role of reactive metabolites in drug-induced hepatotoxicity: state of the science. Expert Opin Drug Metab Toxicol 2008; 4: 14151427.
  • 6
    Davern TJ 2nd, James LP, Hinson JA, Polson J, Larson AM, Fontana RJ, Lalani E, Munoz S, Shakil AO, Lee WM. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 2006; 130: 687694.
  • 7
    Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005; 4: 489499.
  • 8
    Halegoua-De Marzio D, Navarro VJ. Drug-induced hepatotoxicity in humans. Curr Opin Drug Discov Devel 2008; 11: 5359.
  • 9
    Park BK, Kitteringham NR, Maggs JL, Pirmohamed M, Williams DP. The role of metabolic activation in drug-induced hepatotoxicity. Annu Rev Pharmacol Toxicol 2005; 45: 177202.
  • 10
    Park BK, Pirmohamed M, Kitteringham NR. The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity. Pharmacol Ther 1995; 68: 385424.
  • 11
    Guguen-Guillouzo C, Guillouzo A. General review on in vitro hepatocyte models and their applications. Methods Mol Biol 2010; 640: 140.
  • 12
    Sahi J, Grepper S, Smith C. Hepatocytes as a tool in drug metabolism, transport and safety evaluations in drug discovery. Curr Drug Discov Technol 2010; 7: 188198.
  • 13
    Gomez-Lechon 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: 443462.
  • 14
    LeCluyse EL. Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation. Eur J Pharm Sci 2001; 13: 343368.
  • 15
    Kalgutkar AS, Soglia JR. Minimising the potential for metabolic activation in drug discovery. Expert Opin Drug Metab Toxicol 2005; 1: 91142.
  • 16
    Chen Q, Cederbaum AI. Cytotoxicity and apoptosis produced by cytochrome P450 2E1 in Hep G2 cells. Mol Pharmacol 1998; 53: 638648.
  • 17
    Dai Y, Rashba-Step J, Cederbaum AI. Stable expression of human cytochrome P4502E1 in HepG2 cells: characterization of catalytic activities and production of reactive oxygen intermediates. Biochemistry 1993; 32: 69286937.
  • 18
    Goldring CE, Kitteringham NR, Jenkins R, Lovatt CA, Randle LE, Abdullah A, Owen A, Liu X, Butler PJ, Williams DP, Metcalfe P, Berens C, Hillen W, Foster B, Simpson A, McLellan L, Park BK. Development of a transactivator in hepatoma cells that allows expression of phase I, phase II, and chemical defense genes. Am J Physiol Cell Physiol 2006; 290: C104115.
  • 19
    Pfeifer AM, Cole KE, Smoot DT, Weston A, Groopman JD, Shields PG, Vignaud JM, Juillerat M, Lipsky MM, Trump BF, Lechner JF, Harris CC. Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. Proc Natl Acad Sci U S A 1993; 90: 51235127.
  • 20
    Mace K, Aguilar F, Wang JS, Vautravers P, Gomez-Lechon M, Gonzalez FJ, Groopman J, Harris CC, Pfeifer AM. Aflatoxin B1-induced DNA adduct formation and p53 mutations in CYP450-expressing human liver cell lines. Carcinogenesis 1997; 18: 12911297.
  • 21
    Singh S, Kumar V, Singh P, Banerjee BD, Rautela RS, Grover SS, Rawat DS, Pasha ST, Jain SK, Rai A. Influence of CYP2C9, GSTM1, GSTT1 and NAT2 genetic polymorphisms on DNA damage in workers occupationally exposed to organophosphate pesticides. Mutat Res 2011; 740: 101108.
  • 22
    Tekin D, Kayaalti Z, Soylemezoglu T. The effects of metallothionein 2A polymorphism on lead metabolism: are pregnant women with a heterozygote genotype for metallothionein 2A polymorphism and their newborns at risk of having higher blood lead levels? Int Arch Occup Environ Health 2011; DOI: 10.1007/s00420-011-0711-y. [Epub ahead of print].
  • 23
    Wilffert B, Swen J, Mulder H, Touw D. Maitland-Van der Zee AH, Deneer V. From evidence based medicine to mechanism based medicine. Reviewing the role of pharmacogenetics. Int J Clin Pharmacol 2011; 33: 39.
  • 24
    Celander MC, Goldstone JV, Denslow ND, Iguchi T, Kille P, Meyerhoff RD, Smith BA, Hutchinson TH, Wheeler JR. Species extrapolation for the 21st century. Environ Toxicol Chem 2011; 30: 5263.
  • 25
    Lee EW, Lai Y, Zhang H, Unadkat JD. Identification of the mitochondrial targeting signal of the human equilibrative nucleoside transporter 1 (hENT1): implications for interspecies differences in mitochondrial toxicity of fialuridine. J Biol Chem 2006; 281: 1670016706.
  • 26
    Saldana-Ruiz S, Soler-Martin C, Llorens J. Role of CYP2E1-mediated metabolism in the acute and vestibular toxicities of nineteen nitriles in the mouse. Toxicol Lett 2012; 208: 125132.
  • 27
    Wobus AM, Guan K, Yang HT, Boheler KR. Embryonic stem cells as a model to study cardiac, skeletal muscle, and vascular smooth muscle cell differentiation. Methods Mol Biol 2002; 185: 127156.
  • 28
    Hamazaki T, Iiboshi Y, Oka M, Papst PJ, Meacham AM, Zon LI, Terada N. Hepatic maturation in differentiating embryonic stem cells in vitro. FEBS Lett 2001; 497: 1519.
  • 29
    Vittet D, Prandini MH, Berthier R, Schweitzer A, Martin-Sisteron H, Uzan G, Dejana E. Embryonic stem cells differentiate in vitro to endothelial cells through successive maturation steps. Blood 1996; 88: 34243431.
  • 30
    Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 2001; 292: 13891394.
  • 31
    Bielby RC, Boccaccini AR, Polak JM, Buttery LD. In vitro differentiation and in vivo mineralization of osteogenic cells derived from human embryonic stem cells. Tissue Eng 2004; 10: 15181525.
  • 32
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663676.
  • 33
    Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA. Human induced pluripotent stem cells free of vector and transgene sequences. Science 2009; 324: 797801.
  • 34
    Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009; 458: 771775.
  • 35
    Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hamalainen R, Cowling R, Wang W, Liu P, Gertsenstein M, Kaji K, Sung HK, Nagy A. PiggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009; 458: 766770.
  • 36
    Yusa K, Rad R, Takeda J, Bradley A. Generation of transgene-free induced pluripotent mouse stem cells by the piggyBac transposon. Nat Methods 2009; 6: 363369.
  • 37
    Jia F, Wilson KD, Sun N, Gupta DM, Huang M, Li Z, Panetta NJ, Chen ZY, Robbins RC, Kay MA, Longaker MT, Wu JC. A nonviral minicircle vector for deriving human iPS cells. Nat Methods 2010; 7: 197199.
  • 38
    Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, Ko S, Yang E, Cha KY, Lanza R, Kim KS. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 2009; 4: 472476.
  • 39
    Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, Trauger S, Bien G, Yao S, Zhu Y, Siuzdak G, Scholer HR, Duan L, Ding S. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 2009; 4: 381384.
  • 40
    Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan C, Schlaeger TM, Rossi DJ. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 2010; 7: 618630.
  • 41
    Huangfu D, Maehr R, Guo W, Eijkelenboom A, Snitow M, Chen AE, Melton DA. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 2008; 26: 795797.
  • 42
    Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, Muhlestein W, Melton DA. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 2008; 26: 12691275.
  • 43
    Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, Bernstein BE, Jaenisch R, Lander ES, Meissner A. Dissecting direct reprogramming through integrative genomic analysis. Nature 2008; 454: 4955.
  • 44
    Zhu S, Li W, Zhou H, Wei W, Ambasudhan R, Lin T, Kim J, Zhang K, Ding S. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 2010; 7: 651655.
  • 45
    Miyoshi N, Ishii H, Nagano H, Haraguchi N, Dewi DL, Kano Y, Nishikawa S, Tanemura M, Mimori K, Tanaka F, Saito T, Nishimura J, Takemasa I, Mizushima T, Ikeda M, Yamamoto H, Sekimoto M, Doki Y, Mori M. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 2011; 8: 633638.
  • 46
    Anokye-Danso F, Trivedi CM, Juhr D, Gupta M, Cui Z, Tian Y, Zhang Y, Yang W, Gruber PJ, Epstein JA, Morrisey EE. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 2011; 8: 376388.
  • 47
    Prescott C. The business of exploiting induced pluripotent stem cells. Philos Trans R Soc Lond B Biol Sci 2011; 366: 23232328.
  • 48
    Bahadur G, Morrison M. Patenting human pluripotent cells: balancing commercial, academic and ethical interests. Hum Reprod 2010; 25: 1421.
  • 49
    Baxter MA, Rowe C, Alder J, Harrison S, Hanley KP, Park BK, Kitteringham NR, Goldring CE, Hanley NA. Generating hepatic cell lineages from pluripotent stem cells for drug toxicity screening. Stem Cell Res 2010; 5: 422.
  • 50
    Cai J, Zhao Y, Liu Y, Ye F, Song Z, Qin H, Meng S, Chen Y, Zhou R, Song X, Guo Y, Ding M, Deng H. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 2007; 45: 12291239.
  • 51
    Ek M, Soderdahl T, Kuppers-Munther B, Edsbagge J, Andersson TB, Bjorquist P, Cotgreave I, Jernstrom B, Ingelman-Sundberg M, Johansson I. Expression of drug metabolizing enzymes in hepatocyte-like cells derived from human embryonic stem cells. Biochem Pharmacol 2007; 74: 496503.
  • 52
    Soderdahl T, Kuppers-Munther B, Heins N, Edsbagge J, Bjorquist P, Cotgreave I, Jernstrom B. Glutathione transferases in hepatocyte-like cells derived from human embryonic stem cells. Toxicol In Vitro 2007; 21: 929937.
  • 53
    Hay DC, Fletcher J, Payne C, Terrace JD, Gallagher RC, Snoeys J, Black JR, Wojtacha D, Samuel K, Hannoun Z, Pryde A, Filippi C, Currie IS, Forbes SJ, Ross JA, Newsome PN, Iredale JP. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proc Natl Acad Sci U S A 2008; 105: 1230112306.
  • 54
    Shiraki N, Umeda K, Sakashita N, Takeya M, Kume K, Kume S. Differentiation of mouse and human embryonic stem cells into hepatic lineages. Genes Cells 2008; 13: 731746.
  • 55
    Agarwal S, Holton KL, Lanza R. Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells 2008; 26: 11171127.
  • 56
    Moore RN, Moghe PV. Expedited growth factor-mediated specification of human embryonic stem cells toward the hepatic lineage. Stem Cell Res 2009; 3: 5162.
  • 57
    Basma H, Soto-Gutierrez A, Yannam GR, Liu L, Ito R, Yamamoto T, Ellis E, Carson SD, Sato S, Chen Y, Muirhead D, Navarro-Alvarez N, Wong RJ, Roy-Chowdhury J, Platt JL, Mercer DF, Miller JD, Strom SC, Kobayashi N, Fox IJ. Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology 2009; 136: 990999.
  • 58
    Song Z, Cai J, Liu Y, Zhao D, Yong J, Duo S, Song X, Guo Y, Zhao Y, Qin H, Yin X, Wu C, Che J, Lu S, Ding M, Deng H. Efficient generation of hepatocyte-like cells from human induced pluripotent stem cells. Cell Res 2009; 19: 12331242.
  • 59
    Duan Y, Ma X, Zou WEI, Wang C, Bahbahan IS, Ahuja TP, Tolstikov V, Zern MA. Differentiation and characterization of metabolically functioning hepatocytes from human embryonic stem cells. Stem Cells 2010; 28: 674686.
  • 60
    Synnergren J, Heins N, Brolen G, Eriksson G, Lindahl A, Hyllner J, Olsson B, Sartipy P, Bjorquist P. Transcriptional profiling of human embryonic stem cells differentiating to definitive and primitive endoderm and further toward the hepatic lineage. Stem Cells Dev 2010; 19: 961978.
  • 61
    Touboul T, Hannan NR, Corbineau S, Martinez A, Martinet C, Branchereau S, Mainot S, Strick-Marchand H, Pedersen R, Di Santo J, Weber A, Vallier L. Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development. Hepatology 2010; 51: 17541765.
  • 62
    Brolen G, Sivertsson L, Bjorquist P, Eriksson G, Ek M, Semb H, Johansson I, Andersson TB, Ingelman-Sundberg M, Heins N. Hepatocyte-like cells derived from human embryonic stem cells specifically via definitive endoderm and a progenitor stage. J Biotechnol 2010; 145: 284294.
  • 63
    Liu H, Ye Z, Kim Y, Sharkis S, Jang YY. Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes. Hepatology 2010; 51: 18101819.
  • 64
    Bone HK, Nelson AS, Goldring CE, Tosh D, Welham MJ. A novel chemically directed route for the generation of definitive endoderm from human embryonic stem cells based on inhibition of GSK-3. J Cell Sci 2011; 124: 19922000.
  • 65
    Si-Tayeb K, Noto FK, Nagaoka M, Li J, Battle MA, Duris C, North PE, Dalton S, Duncan SA. Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 2010; 51: 297305.
  • 66
    Zhang S, Chen S, Li W, Guo X, Zhao P, Xu J, Chen Y, Pan Q, Liu X, Zychlinski D, Lu H, Tortorella MD, Schambach A, Wang Y, Pei D, Esteban MA. Rescue of ATP7B function in hepatocyte-like cells from Wilson's disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin. Hum Mol Genet 2011; 20: 31763187.
  • 67
    Chen YF, Tseng CY, Wang HW, Kuo HC, Yang VW, Lee OK. Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol. Hepatology 2012; 55: 11931203.
  • 68
    Sancho-Bru P, Najimi M, Caruso M, Pauwelyn K, Cantz T, Forbes S, Roskams T, Ott M, Gehling U, Sokal E, Verfaillie CM, Muraca M. Stem and progenitor cells for liver repopulation: can we standardise the process from bench to bedside? Gut 2009; 58: 594603.
  • 69
    Yildirimman R, Brolen G, Vilardell M, Eriksson G, Synnergren J, Gmuender H, Kamburov A, Ingelman-Sundberg M, Castell J, Lahoz A, Kleinjans J, van Delft J, Bjorquist P, Herwig R. Human embryonic stem cell derived hepatocyte-like cells as a tool for in vitro hazard assessment of chemical carcinogenicity. Toxicol Sci 2011; 124: 278290.
  • 70
    Wobus AM, Loser P. Present state and future perspectives of using pluripotent stem cells in toxicology research. Arch Toxicol 2011; 85: 79117.
  • 71
    Robinton DA, Daley GQ. The promise of induced pluripotent stem cells in research and therapy. Nature 2012; 481: 295305.
  • 72
    Hewitt NJ, Lechon MJ, Houston JB, Hallifax D, Brown HS, Maurel P, Kenna JG, Gustavsson L, Lohmann C, Skonberg C, Guillouzo A, Tuschl G, Li AP, LeCluyse E, Groothuis GM, Hengstler JG. 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: 159234.
  • 73
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281297.
  • 74
    Hobert O. Gene regulation by transcription factors and microRNAs. Science 2008; 319: 17851786.
  • 75
    Lin SL, Chang DC, Lin CH, Ying SY, Leu D, Wu DT. Regulation of somatic cell reprogramming through inducible mir-302 expression. Nucleic Acids Res 2011; 39: 10541065.
  • 76
    Pfaff N, Fiedler J, Holzmann A, Schambach A, Moritz T, Cantz T, Thum T. miRNA screening reveals a new miRNA family stimulating iPS cell generation via regulation of Meox2. EMBO Rep 2011; 12: 11531159.
  • 77
    Subramanyam D, Lamouille S, Judson RL, Liu JY, Bucay N, Derynck R, Blelloch R. Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biotechnol 2011; 29: 443448.
  • 78
    Barrilleaux B, Knoepfler PS. Inducing iPSCs to escape the dish. Cell Stem Cell 2011; 9: 103111.
  • 79
    Liao B, Bao X, Liu L, Feng S, Zovoilis A, Liu W, Xue Y, Cai J, Guo X, Qin B, Zhang R, Wu J, Lai L, Teng M, Niu L, Zhang B, Esteban MA, Pei D. MicroRNA cluster 302–367 enhances somatic cell reprogramming by accelerating a mesenchymal-to-epithelial transition. J Biol Chem 2011; 286: 1735917364.
  • 80
    Bar-Nur O, Russ HA, Efrat S, Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell 2011; 9: 1723.
  • 81
    Sullivan GJ, Hay DC, Park I-H, Fletcher J, Hannoun Z, Payne CM, Dalgetty D, Black JR, Ross JA, Samuel K, Wang G, Daley GQ, Lee J-H, Church GM, Forbes SJ, Iredale JP, Wilmut I. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology 2010; 51: 329335.
  • 82
    Ghodsizadeh A, Taei A, Totonchi M, Seifinejad A, Gourabi H, Pournasr B, Aghdami N, Malekzadeh R, Almadani N, Salekdeh GH, Baharvand H. Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev 2010; 6: 622632.
  • 83
    Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple R, Weber A, Lomas DA, Vallier L. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest 2010; 120: 31273136.
  • 84
    Yusa K, Rashid ST, Strick-Marchand H, Varela I, Liu P-Q, Paschon DE, Miranda E, Ordonez A, Hannan NRF, Rouhani FJ, Darche S, Alexander G, Marciniak SJ, Fusaki N, Hasegawa M, Holmes MC, Di Santo JP, Lomas DA, Bradley A, Vallier L. Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells. Nature 2011; 478: 391394.
  • 85
    Jozefczuk J, Prigione A, Chavez L, Adjaye J. Comparative analysis of human embryonic stem cell and induced pluripotent stem cell-derived hepatocyte-like cells reveals current drawbacks and possible strategies for improved differentiation. Stem Cells Dev 2011; 20: 12591275.
  • 86
    Newman AM, Cooper JB. Lab-specific gene expression signatures in pluripotent stem cells. Cell Stem Cell 2010; 7: 258262.
  • 87
    Shirahashi H, Wu J, Yamamoto N, Catana A, Wege H, Wager B, Okita K, Zern MA. Differentiation of human and mouse embryonic stem cells along a hepatocyte lineage. Cell Transplant 2004; 13: 197211.