{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:46:55Z","timestamp":1790732815912,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,11,1]]},"DOI":"10.1093\/toxsci\/kfu173","type":"journal-article","created":{"date-parts":[[2014,8,22]],"date-time":"2014-08-22T02:20:20Z","timestamp":1408674020000},"page":"137-157","source":"Crossref","is-referenced-by-count":80,"title":["Human Hepatocytes Support the Hypertrophic but not the Hyperplastic Response to the Murine Nongenotoxic Hepatocarcinogen Sodium Phenobarbital in an In Vivo Study Using a Chimeric Mouse with Humanized Liver"],"prefix":"10.1093","volume":"142","author":[{"given":"Tomoya","family":"Yamada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Okuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Kushida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayo","family":"Sumida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayato","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirohisa","family":"Nagahori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takako","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian G.","family":"Lake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel M.","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Kawamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,8,21]]},"reference":[{"key":"key\n\t\t\t\t20171012053457_B1","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1080\/10408440600977677","article-title":"IPCS framework for analyzing the relevance of a cancer mode of action for humans","volume":"36","author":"Boobis","year":"2006","journal-title":"Crit. Rev. Toxicol."},{"key":"key\n\t\t\t\t20171012053457_B2","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."},{"key":"key\n\t\t\t\t20171012053457_B3","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1093\/toxsci\/kfu099","article-title":"Phenobarbital-mediated tumor promotion in transgenic mice with humanized CAR and PXR","volume":"140","author":"Braeuning","year":"2014","journal-title":"Toxicol Sci."},{"key":"key\n\t\t\t\t20171012053457_B4","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1177\/0192623310363813","article-title":"Evaluation of possible carcinogenic risk to humans based on liver tumors in rodent assays: The two-year bioassay is no longer necessary","volume":"38","author":"Cohen","year":"2010","journal-title":"Toxicol. Pathol."},{"key":"key\n\t\t\t\t20171012053457_B5","doi-asserted-by":"crossref","first-page":"S76","DOI":"10.1093\/toxsci\/kfq365","article-title":"Chemical carcinogenesis","volume":"120","author":"Cohen","year":"2011","journal-title":"Toxicol. Sci."},{"key":"key\n\t\t\t\t20171012053457_B6","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1093\/toxsci\/kfh073","article-title":"Evaluating the human relevance of chemically induced animal tumors","volume":"78","author":"Cohen","year":"2004","journal-title":"Toxicol. Sci."},{"key":"key\n\t\t\t\t20171012053457_B7","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1002\/hep.20883","article-title":"Gadd45beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia","volume":"42","author":"Columbano","year":"2005","journal-title":"Hepatology"},{"key":"key\n\t\t\t\t20171012053457_B8","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1093\/toxsci\/kfp006","article-title":"Mode of action analysis for the synthetic pyrethroid metofluthrin-induced rat liver tumors: Evidence for hepatic CYP2B induction and hepatocyte proliferation","volume":"108","author":"Deguchi","year":"2009","journal-title":"Toxicol. Sci."},{"key":"key\n\t\t\t\t20171012053457_B9","doi-asserted-by":"crossref","first-page":"64","DOI":"10.3109\/10408444.2013.835786","article-title":"Mode of action and human relevance analysis for nuclear-receptor mediated liver toxicity: A case study with phenobarbaital as a model constitutive androstane receptor (CAR) activator","volume":"44","author":"Elcombe","year":"2014","journal-title":"Crit. Rev. Toxicol."},{"key":"key\n\t\t\t\t20171012053457_B10","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3109\/00498254.2013.867553","article-title":"Chimeric rodents with humanized liver: Bridging the preclinical\/clinical trial gap in ADME\/toxicity studies","volume":"44","author":"Foster","year":"2014","journal-title":"Xenobiotica"},{"key":"key\n\t\t\t\t20171012053457_B11","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1002\/ijc.24545","article-title":"Epidemiologic evaluation of pharmaceuticals with limited evidence of carcinogenicity","volume":"125","author":"Friedman","year":"2009","journal-title":"Int. J. Cancer"},{"key":"key\n\t\t\t\t20171012053457_B12","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.tox.2009.01.007","article-title":"Comparison of the effects of the synthetic pyrethroid Metofluthrin and phenobarbital on CYP2B form induction and replicative DNA synthesis in cultured rat and human hepatocytes","volume":"258","author":"Hirose","year":"2009","journal-title":"Toxicology"},{"key":"key\n\t\t\t\t20171012053457_B13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1093\/toxsci\/kfj001","article-title":"Mode of action in relevance of rodent liver tumors to human cancer risk","volume":"89","author":"Holsapple","year":"2006","journal-title":"Toxicol. Sci."},{"key":"key\n\t\t\t\t20171012053457_B14","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1210\/me.2004-0520","article-title":"Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor","volume":"19","author":"Huang","year":"2005","journal-title":"Mol. Endocrinol."},{"key":"key\n\t\t\t\t20171012053457_B15","first-page":"161","article-title":"Some thyrotropic agents: phenobarbital and its sodium salt","volume":"79","author":"IARC","year":"2001","journal-title":"IARC Monogr. Eval. Carcinog. Risks Hum."},{"key":"key\n\t\t\t\t20171012053457_B16","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S0940-2993(96)80039-X","article-title":"Proliferation markers","volume":"48","author":"Iatropoulos","year":"1996","journal-title":"Exp. Toxicol. Pathol."},{"key":"key\n\t\t\t\t20171012053457_B17","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1016\/j.fct.2009.03.014","article-title":"Effect of chronic phenobarbitone administration on liver tumour formation in the C57BL\/10J mouse","volume":"47","author":"Jones","year":"2009","journal-title":"Food Chem. Toxicol."},{"key":"key\n\t\t\t\t20171012053457_B18","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3109\/00498254.2013.868062","article-title":"Current status of prediction of drug disposition and toxicity in humans using chimeric mice with humanized liver","volume":"44","author":"Kitamura","year":"2014","journal-title":"Xenobiotica"},{"key":"key\n\t\t\t\t20171012053457_B19","first-page":"183","article-title":"Preparation and characterization of microsomal fractions for study of xenobiotic metabolism.","volume-title":"Biochemical Toxicology","author":"Lake","year":"1987"},{"key":"key\n\t\t\t\t20171012053457_B20","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1080\/00498250903098184","article-title":"Species differences in the hepatic effects of inducers of CYP2B and CYP4A subfamily forms: Relationship to rodent liver tumour formation","volume":"39","author":"Lake","year":"2009","journal-title":"Xenobiotica"},{"key":"key\n\t\t\t\t20171012053457_B21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/CEJ.0b013e32836014c8","article-title":"A review of epidemiological data on epilepsy, phenobarbital, and risk of liver cancer","volume":"23","author":"La Vecchia","year":"2014","journal-title":"Eur. J. Cancer Prev."},{"key":"key\n\t\t\t\t20171012053457_B22","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1093\/toxsci\/kfu038","article-title":"Phenobarbital induces cell cycle transcriptional responses in humanized CAR\/PXR mouse liver","volume":"138","author":"Luisier","year":"2014","journal-title":"Toxicol. Sci."},{"key":"key\n\t\t\t\t20171012053457_B23","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1677\/JOE-07-0126","article-title":"GH enhances proliferation of human hepatocytes grafted into immunodeficient mice with damaged liver","volume":"194","author":"Masumoto","year":"2007","journal-title":"J. Endocrinol."},{"key":"key\n\t\t\t\t20171012053457_B24","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1080\/713608373","article-title":"A framework for human relevance analysis of information on carcinogenic modes of action","volume":"33","author":"Meek","year":"2003","journal-title":"Crit. Rev. Toxicol."},{"key":"key\n\t\t\t\t20171012053457_B25","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1038\/90968","article-title":"Hepatitis C virus replication in mice with chimeric human livers","volume":"7","author":"Mercer","year":"2001","journal-title":"Nat. Med."},{"key":"key\n\t\t\t\t20171012053457_B26","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1515\/dmdi-2013-0009","article-title":"An update on the constitutive androstane receptor (CAR)","volume":"28","author":"Molnar","year":"2013","journal-title":"Drug Metabol. Drug Interact."},{"key":"key\n\t\t\t\t20171012053457_B27","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1006\/rtph.1993.1048","article-title":"The paradoxical lack of interspecies correlation between plasma concentrations and chemical carcinogenicity","volume":"18","author":"Monro","year":"1993","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"key\n\t\t\t\t20171012053457_B28","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0304-4165(02)00481-6","article-title":"Functional and structural comparison of PXR and CAR","volume":"1619","author":"Moore","year":"2003","journal-title":"Biochim. Biophys. Acta"},{"key":"key\n\t\t\t\t20171012053457_B29","doi-asserted-by":"crossref","first-page":"19029","DOI":"10.1074\/jbc.M703112200","article-title":"Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7\/JNKK2","volume":"282","author":"Papa","year":"2007","journal-title":"J. Biol. Chem."},{"key":"key\n\t\t\t\t20171012053457_B30","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/ncb1093","article-title":"Gadd45[beta] mediates the NF-[kappa]B suppression of JNK signalling by targeting MKK7\/JNKK2","volume":"6","author":"Papa","year":"2004","journal-title":"Nat. Cell Biol."},{"key":"key\n\t\t\t\t20171012053457_B31","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1172\/JCI33913","article-title":"Gadd45beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling","volume":"118","author":"Papa","year":"2008","journal-title":"J. Clin. Iinvest."},{"key":"key\n\t\t\t\t20171012053457_B32","first-page":"1143","article-title":"Testing for induction of DNA synthesis in human hepatocyte primary cultures by rat liver tumor promoters","volume":"51","author":"Parzefall","year":"1991","journal-title":"Cancer Res."},{"key":"key\n\t\t\t\t20171012053457_B33","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nature02924","article-title":"NF-[kappa]B functions as a tumour promoter in inflammation-associated cancer","volume":"431","author":"Pikarsky","year":"2004","journal-title":"Nature"},{"key":"key\n\t\t\t\t20171012053457_B34","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/toxsci\/kfq118","article-title":"Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo","volume":"116","author":"Ross","year":"2010","journal-title":"Toxicol. Sci."},{"key":"key\n\t\t\t\t20171012053457_B35","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/0092-8674(91)90615-6","article-title":"Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene","volume":"66","author":"Sandgren","year":"1991","journal-title":"Cell"},{"key":"key\n\t\t\t\t20171012053457_B36","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/(SICI)1097-4652(200003)182:3<311::AID-JCP1>3.0.CO;2-9","article-title":"The Ki-67 protein: From the known and the unknown","volume":"182","author":"Scholzen","year":"2000","journal-title":"J. Cell. Physiol."},{"key":"key\n\t\t\t\t20171012053457_B37","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1006\/rtph.2001.1493","article-title":"IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis","volume":"34","author":"Sonich-Mullin","year":"2001","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"key\n\t\t\t\t20171012053457_B38","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1073\/pnas.92.4.959","article-title":"A single arginine residue determines species specificity of the human growth hormone receptor","volume":"92","author":"Souza","year":"1995","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"key\n\t\t\t\t20171012053457_B39","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1210\/en.2010-0953","article-title":"Growth hormone-dependent pathogenesis of human hepatic steatosis in a novel mouse model bearing a human hepatocyte-repopulated liver","volume":"152","author":"Tateno","year":"2011","journal-title":"Endocrinology"},{"key":"key\n\t\t\t\t20171012053457_B40","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/labinvest.2012.158","article-title":"Morphological and microarray analyses of human hepatocytes from xenogeneic host livers","volume":"93","author":"Tateno","year":"2013","journal-title":"Lab. Invest."},{"key":"key\n\t\t\t\t20171012053457_B41","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/S0002-9440(10)63352-4","article-title":"Near completely humanized liver in mice shows human-type metabolic responses to drugs","volume":"165","author":"Tateno","year":"2004","journal-title":"Am. J. Pathol."},{"key":"key\n\t\t\t\t20171012053457_B42","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1172\/JCI38760","article-title":"Gadd45beta is an inducible coactivator of transcription that facilitates rapid liver growth in mice","volume":"121","author":"Tian","year":"2011","journal-title":"J. Clin. Invest."},{"key":"key\n\t\t\t\t20171012053457_B43","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.addr.2010.08.006","article-title":"Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR","volume":"62","author":"Tolson","year":"2010","journal-title":"Adv. Drug Deliv. Rev."},{"key":"key\n\t\t\t\t20171012053457_B44","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1038\/35038112","article-title":"The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism","volume":"407","author":"Wei","year":"2000","journal-title":"Nature"},{"key":"key\n\t\t\t\t20171012053457_B45","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/0163-7258(96)00067-8","article-title":"Phenobarbital mechanistic data and risk assessment: enzyme induction, enhanced cell proliferation, and tumor promotion","volume":"71","author":"Whysner","year":"1996","journal-title":"Pharmacol. Ther."},{"key":"key\n\t\t\t\t20171012053457_B46","doi-asserted-by":"crossref","first-page":"e10121","DOI":"10.1371\/journal.pone.0010121","article-title":"Nuclear receptor CAR represses TNFalpha-induced cell death by interacting with the anti-apoptotic GADD45B","volume":"5","author":"Yamamoto","year":"2010","journal-title":"PLoS ONE"},{"key":"key\n\t\t\t\t20171012053457_B47","doi-asserted-by":"crossref","first-page":"7197","DOI":"10.1158\/0008-5472.CAN-04-1459","article-title":"The orphan nuclear receptor constitutive active\/androstane receptor is essential for liver tumor promotion by phenobarbital in mice","volume":"64","author":"Yamamoto","year":"2004","journal-title":"Cancer Res."}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/toxsci\/article-pdf\/142\/1\/137\/16690449\/kfu173.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2017,10,12]],"date-time":"2017-10-12T05:35:06Z","timestamp":1507786506000},"score":1,"resource":{"primary":{"URL":"http:\/\/academic.oup.com\/toxsci\/article\/142\/1\/137\/1709884\/Human-Hepatocytes-Support-the-Hypertrophic-but-not"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8,21]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,8,21]]},"published-print":{"date-parts":[[2014,11,1]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfu173","relation":{},"ISSN":["1096-0929","1096-6080"],"issn-type":[{"value":"1096-0929","type":"electronic"},{"value":"1096-6080","type":"print"}],"subject":[],"published-other":{"date-parts":[[2014,11]]},"published":{"date-parts":[[2014,8,21]]}}}