In this report, metabolically competent in vitro systems have been reviewed, in the context of drug metabolising enzyme induction. Based on the experience of the scientists involved, a thorough survey of the literature on metabolically competent long-term culture models was performed. Following this, a prevalidation proposal for the use of the collagen gel sandwich hepatocyte culture system for drug metabolising enzyme induction was designed, focusing on the induction of the cytochrome P450 enzymes as the principal enzymes of interest. The ultimate goal of this prevalidation proposal is to provide industry and academia with a metabolically competent in vitro alternative for long-term studies. In an initial phase, the prevalidation study will be limited to the investigation of induction. However, proposals for other long-term applications of these systems should be forwarded to the European Centre for the Validation of Alternative Methods for consideration. The prevalidation proposal deals with several issues, including: a) species; b) practical prevalidation methodology; c) enzyme inducers; and d) advantages of working with independent expert laboratories. Since it is preferable to include other alternative tests for drug metabolising enzyme induction, when such tests arise, it is recommended that they meet the same level of development as for the collagen gel sandwich long-term hepatocyte system. Those tests which do so should begin the prevalidation and validation process.
BlaauboerB.J., BoobisA.R., CastellJ.V., CoeckeS., GroothuisG.M.M., GuillouzoA., HallT.J., HawksworthG.M., LorenzonG., MiltenburgerH.G., RogiersV., SkettP., VillaP., & WiebelF.J. (1994). The practical applicability of hepatocyte cultures in routine testing. The report and recommendations of ECVAM workshop 1. ATLA22, 231–241.
2.
FDA (1997). Guidance for Industry: Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies In Vitro.Washington, DC, USA: FDA.
3.
PelkonenO., MäenpääJ., TaavitsainenP., RautioA., & RaunioH. (1998). Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica28, 1203–1253.
4.
DaviesT.S., & KluweW.M. (1998). Preclinical toxicological evaluation of sertraline hydrochloride. Drug Chemical Toxicology21, 521–537.
5.
MattesW.B., & LiA.P. (1997). Quantitative reverse transcriptase/PCR assay for the measurement of induction in cultured hepatocytes. Chemico-Biological Interactions107, 47–61.
6.
GuengerichF.P., JohnsonW.W., ShimadaT., UengY.F., YamazakiH., & LangouetS. (1998). Activation and detoxication of aflatoxin B1. Mutation Research402, 121–128.
7.
PaoliniM., PozzettiL., PeroccoP., MazzulloM., & Cantelli-FortiG. (1999). Molecular non-genetic biomarkers of effect related to methyl thiophanate cocarcinogenesis: organ- and sex-specific cytochrome P450 induction in the rat. Cancer Letters135, 203–213.
DograS.C., WhitelawM.L., & MayB.K. (1998). Transcriptional activation of cytochrome P450 genes by different classes of chemical inducers. Clinical Experimental Pharmacology and Physiology25, 1–9.
10.
RamanaK.V., & KohliK.K. (1998). Gene regulation of cytochrome P450: an overview. Indian Journal of Experimental Biology36, 437–446.
11.
KemperB. (1998). Regulation of cytochrome P450 gene transcription by phenobarbital. Progress in Nucleic Acid Research and Molecular Biology61, 23–64.
12.
EltomS.E., ZhangL., & JefcoateC.R. (1999). Regulation of cytochrome P450 (CYP) 1B1 in mouse Hepa-1 variant cell lines: a possible role for aryl hydrocarbon receptor nuclear translocator (ARNT) as a suppressor of CYP1B1 gene expression. Molecular Pharmacology55, 594–604.
13.
ZaherH., & SvenssonC.K. (1994). Glucocorticoid induction of hepatic acetyl CoA: arylamine N-acetyltransferase activity in the rat. Research Communications in Chemical Pathology and Pharmacology83, 195–208.
14.
FeiP., MatwyshynG.A., RushmoreT.H., & KongA.N. (1996). Transcription regulation of rat glutathione S-transferase Ya subunit gene expression by chemopreventive agents. Pharmacology Research13, 1043–1048.
15.
MurphyS.E., NunesM.G., & HatalaM.A. (1997). Effects of phenobarbital and 3-methyl-cholanthrene induction on the formation of three glucuronide metabolites of 4-(methylni-trosamino)-1-(3-pyridyl)-1-butanone, NNK. Chemico-Biological Interactions103, 153–166.
16.
FalknerK.C., RushmoreT.H., LinderM.W., & ProughR.A. (1998). Negative regulation of the rat glutathione S-transferase A2 gene by glucocorticoids involves a canonical glucocorticoid consensus sequence. Molecular Pharmacology53, 1016–1026.
17.
StrassburgC.P., NguyenN., MannsM.P., & TukeyR.H. (1999). UDP-glucuronosyltrans-ferase activity in human liver and colon. Gastroenterology116, 149–160.
18.
WhalenR., & BoyerT.D. (1998). Human glutathione S-transferases. Seminars on Liver Diseases18, 345–358.
19.
GulickA.M., & FahlW.E. (1995). Mammalian glutathione S-transferase: regulation of an enzyme system to achieve chemotherapeutic efficacy. Pharmacology and Therapeutics66, 237–257.
20.
DanielV. (1993). Glutathione S-transferases: gene structure and regulation of expression. CRC Critical Reviews of Biochemical and Molecular Biology28, 173–207.
21.
AinbinderE., BergelsonS., & DanielV. (1997). Signaling pathways in the induction of c-fos and c-jun proto-oncogenes by 3-methylcholan-threne. Receptor Signal Transduction7, 279–289.
22.
DwivediR.S., GruebeleA., & NovakR.F. (1992). Effects of altered calcium homeostasis on the expression of glutathione S-transferase isozymes in primary cultured rat hepatocytes. Biochemical Pharmacology44, 2099–2103.
23.
OinonenT., SaarikoskiS., Husgafvel-PursiainenK., HirvonenA., & LindrosK.O. (1994). Pretranslational induction of cytochrome P4501A enzymes by β-naphthoflavone and 3-methylcholanthrene occurs in different liver zones. Biochemical Pharmacology48, 2189–2197.
24.
LindrosK.O., OinonenT., KettunenE., Sip-pelH., Muro-LuporiC., & KoivusaloM. (1998). Aryl hydrocarbon receptor-associated genes in rat liver: regional coinduction of aldehyde dehydrogenase 3 and glutathione transferase Ya. Biochemical Pharmacology55, 413–421.
25.
SaarikoskiS.T., IkonenT.S., OinonenT., Lin-drosK.O., UlmanenI., & Husgafvel-PursiainenK. (1998). Induction of UDP-glycosyltransferase family 1 genes in rat liver: different patterns of mRNA expression with two inducers, 3-methylcholanthrene and β-naph-thoflavone. Biochemical Pharmacology56, 569–575.
26.
LiA.P., MaurelP., Gómez-LechónM.J., ChengL.C., & Jurima-RometM. (1997). Pre-clinical evaluation of drug–drug interaction potential: present status of the application of primary human hepatocytes in the evaluation of cytochrome P450 induction. Chemico-Biological Interactions107, 5–16.
27.
RogiersV., BlaauboerB., MaurelP., PhillipsI., & ShephardE. (1995). Hepatocyte-based in vitro models and their application in pharmaco-toxicology: report of an EC DGXII meeting with representatives of the European Pharmaceutical Industry. Toxicology in Vitro9, 685–694.
28.
GonzalezF.J., CrespiC.L., & GelboinH.V. (1991). cDNA-expressed human cytochrome P450s: a new age of molecular toxicology and human risk assessment. Mutation Research247, 113–127.
29.
RemmelR.P., & BurchellB. (1993). Validation and use of cloned, expressed human drug-metabolizing enzymes in heterologous cells for analysis of drug metabolism and drug–drug interactions. Biochemical Pharmacology46, 559–556.
30.
TownsendA.J., FieldsW.R., DossA.J., ClapperM.L., DoehmerJ., & MorrowC.S. (1999). Modeling the chemoprotective functions of glutathione S-transferases in cultured cell lines by heterologous expression. Drug Metabolism Reviews31, 43–69.
31.
MacéK., OffordE.F., & PfeifferA. (1997). Drug metabolism and carcinogen activation studies with human genetically engineered cells. In In Vitro Methods in Pharmaceutical Research (ed. CastellJ.V., & Gómez-LechónM.J.), pp. 433–456. London, UK: Academic Press.
RodriguesA.D. (1997). Preclinical drug metabolism in the age of high-throughput screening: an industrial perspective. Pharmaceutical Research14, 1504–1510.
DoehmerJ. (1993). V79 Chinese hamster cells genetically engineered for cytochrome P450 and their use in mutagenicity and metabolism studies. Toxicology82, 105–118.
36.
WrightonS.A., VandenbrandenM., StevensJ.C., ShipleyL.A., RingB.J., RettieA.E., & CashmanJ.R. (1993). In vitro methods for assessing human hepatic drug metabolism: their use in drug development. Drug Metabolism Reviews25, 453–484.
37.
RodriguezA.D. (1994). Use of in vitro human metabolism studies in drug development. Biochemical Pharmacology48, 2147–2156.
38.
BerryM.N., HallsH.J., & GrivellM.B. (1992). Techniques for pharmacological and toxicological studies with isolated hepatocyte suspensions. Life Science51, 1–16.
39.
WortelboerH.M., de KruifC.A., van IerselA.A., FalkeH.E., NoordhoekJ., & BlaauboerB.J. (1990). The isoenzyme pattern of cytochrome P450 in rat hepatocytes in primary culture, comparing different enzyme activities in microsomal incubations and in intact mono-layers. Biochemical Pharmacology40, 2525–2534.
40.
SkettP. (1994). Problems in using isolated and cultured hepatocytes for xenobiotic metabolism/metabolism-based toxicity testing: solutions. Toxicology in Vitro8, 491–504.
41.
DavilaJ.C., & AcostaD. (1993). Preparation of primary monolayer cultures of postnatal rat liver cells for hepatotoxic assessment of xenobiotics. In Methods in Toxicology, Vol. 1A (ed. TysonC.A., & FrazierJ.M.), pp. 244–254. London, UK: Academic Press.
42.
GuillouzoA. (1986). Use of isolated and cultured hepatocytes for xenobiotic metabolism and cytotoxicity studies. In Research in Isolated and Cultured Hepatocytes (ed. GuillouzoA., & Guguen-GuillouzoC.), pp. 313–332. France: John Libbey Eurotext Ltd/Inserm.
43.
VerhoevenC.H., KrebbersS.F., WagenaarsG.N., BooyC.J., GroothuisG.M., OlingaP., & VosR.M. (1998). In vitro and in vivo metabolism of the progestagen Org 30659 in several species. Drug Metabolism and Disposition26, 1102–1112.
44.
RogiersV., VandenbergheY., CallaertsA., VerleyeG., CornetM., MertensK., SonckW., & VercruysseA. (1990). Phase I and Phase II xenobiotic biotransformation in cultures and co-cultures of adult rat hepatocytes. Biochemical Pharmacology40, 1701–1706.
45.
Gómez-LechónM.J., LopezP., DonatoT., MontoyaA., LarrauriA., GimenezP., TrullenqueR., FabraR., & CastellJ.V. (1990). Culture of human hepatocytes from small surgical liver biopsies: biochemical characterization and comparison with in vivo. In Vitro Cellular and Developmental Biology26, 67–74.
46.
DonatoM.T., CastellJ.V., & Gómez-LechónM.J. (1990). Effects of xenobiotics on monooxygenase activities in cultured human hepatocytes. Biochemical Pharmacology39, 1321–1326.
47.
KocarekT.A., SchuetzE.G., & GuzelianP.S. (1993). Expression of multiple forms of cytochrome P450 mRNAs in primary cultures of rat hepatocytes maintained on Matrigel. Molecular Pharmacology43, 328–334.
48.
Lopez-GarciaM.P. (1998). Endogenous nitric oxide is responsible for the early loss of P450 in cultured rat hepatocytes. FEBS Letters438, 145–149.
49.
GreuetJ., PichardL., OurlinJ.C., BonfilsC., DomergueJ., Le TreutP., & MaurelP. (1997). Effect of cell density and epidermal growth factor on the inducible expression of CYP3A and CYP1A genes in human hepatocytes in primary culture. Hepatology25, 1166–1175.
50.
LeCluyseE.L., BullockP.L., & ParkinsonA. (1996). Strategies for restoration and maintenance of normal hepatic structure and function in long-term cultures of rat hepatocytes. Advanced Drug Delivery Reviews22, 133–186.
51.
GuillouzoA., MorelF., RatanasavanhP., ChesnéC., & Guguen-GuillouzoC. (1990). Long-term culture of functional hepatocytes. Toxicology in Vitro4, 415–427.
52.
RogiersV., & VercruysseA. (1993). Rat hepatocyte cultures and co-cultures in biotransformation studies of xenobiotics. Toxicology82, 193–208.
53.
GebhardtR. (1994). Improved drug metabolizing capacity of hepatocytes co-cultured with epithelial cells and maintained in a perifusion system. In Alternatives to Animal Testing. New Ways in the Biomedical Sciences, Trends and Progress (ed. ReinhardtC.), pp. 141–146. Weinheim, Germany: VCH.
54.
GebhardtR., WegnerH., & AlberJ. (1996). Perifusion of co-cultured hepatocytes: optimization of studies on drug metabolism and cytotoxicity in vitro. Cellular Biology and Toxicology12, 57–68.
55.
LiA.P., BarkerG., BeckD., ColburnS., MonsellR., & PellegrinC. (1993). Culturing of primary hepatocytes as entrapped aggregates in a packed bed bioreactor: a potential bioartificial liver. In Vitro Cellular and Developmental Biology29, 249–254.
56.
BrendelK., GandolfiA.J., KrumdieckC.L., & SmithP.F. (1987). Tissue slicing and culturing revisited. Trends in Pharmacological Sciences8, 11–15.
57.
EkinsS. (1996). Past, present and future application of precision-cut liver slices for in vitro xenobiotic metabolism. Drug Metabolism Reviews28, 591–623.
58.
OlingaP., MeremaM.T., HofI.H., De JagerM.H., De JongK.P., SlooffM.J., MeijerD.K., & GroothuisG.M.M. (1998). Effect of cold and warm ischaemia on drug metabolism in isolated hepatocytes and slices from human and monkey liver. Xenobiotica28, 349–360.
59.
VickersA.E.M. (1997). Experimental in vitro models to evaluate hepatotoxicity. In In Vitro Methods on Pharmaceutical Research (ed. CastellJ.V., & Gómez-LechónM.J.), pp. 103–127. London, UK: Academic Press.
60.
BachP.H., VickersA.E.M., BaumannA., BritteboE., CarlileD.J., KosterH.J., LakeB.G., SalmonF., SawyerT.W., & SkibinskiG. (1996). The use of tissue slices for pharmacotoxicology studies. The report and recommendations of ECVAM workshop 20. ATLA24, 893–923.
61.
LakeB.G., BeamandJ.A., JapengaA.C., Ren-wickA., DaviesS., & PriceR.J. (1993). Induction of cytochrome P450-dependent enzyme activities in cultured rat liver slices. Food and Chemical Toxicology31, 377–386.
62.
LakeB.G., CharzatC., TredgerJ.M., RenwickA.B., BeamandJ.A., & PriceR.J. (1996). Induction of cytochrome P450 isoenzymes in cultured precision-cut rat and human liver slices. Xenobiotica26, 297–306.
63.
BeamandJ.A., PriceR.J., CunninghameM.E., & LakeB.G. (1993). Culture of precision-cut liver slices: effect of some peroxisome proliferators. Food and Chemical Toxicology31, 137–147.
64.
LakeB.G., BallS.E., RenwickA.B., TredgerJ.M., KaoJ., BeamandJ.A., & PriceR.J. (1997). Induction of CYP3A isoforms in cultured precision-cut human liver slices. Xenobiotica27, 1165–1173.
65.
LakeB.G., TredgerJ.M., RenwickA.B., BartonP.T., & PriceR.J. (1998). 3,3'-Diindolyl-methane induces CYP1A2 in cultured precision-cut human liver slices. Xenobiotica28, 803–811.
66.
GlocknerR., SteinmetzerP., DrobnerC., & MullerD. (1998). Application of cryopreserved precision-cut liver slices in pharmacotoxicology: principles, literature data and own investigations with special reference to CYP1A1-mRNA induction. Experimental Toxicology and Pathology50, 440–449.
67.
de KanterR., & KosterH.J. (1995). Cryopreservation of rat and monkey liver slices. ATLA23, 653–665.
68.
DonatoM.T., Gómez-LechónM.J., & CastellJ.V. (1992). Co-cultures of hepatocytes: a biological model for long-lasting cultures. In In Vitro Alternatives to Animal Pharmacotoxicology (ed. CastellJ., & Gómez-LechónM.J.), pp. 110–127. Madrid, Spain: Farmaindustria.
69.
MatsumotoA., & YamamotoN. (1993). Characterization of a hepatocyte growth factor derived from nonparenchymal liver cells. Cell Structure and Function18, 87–94.
70.
MorinO., & NormandC. (1986). Long-term maintenance of hepatocyte functional activity in co-culture: requirements for sinusoidal endothelial cells and dexhasone. Journal of Cellular Physiology129, 103–110.
71.
Kuri-HarcuchW., & Mendoza-FigueroaT. (1989). Cultivation of adult rat hepatocytes on 3T3 cells: expression of various liver-differentiated functions. Differentiation41, 148–157.
72.
DonatoM.T., CastellJ.V., & Gómez-LechónM.J. (1991). Co-cultures of hepatocytes with epithelial-like cell lines: expression of drug-bio-transformation activities by hepatocytes. Cell Biology and Toxicology7, 1–14.
73.
MontesanoR., BannikovG., DevronC., KurokiT., Saint-VincentL., & TomatisL. (1980). Neoplastic transformation of rat liver epithelial cells in culture. Annals of the New York Academy of Sciences349, 323–331.
74.
MesnilM., PiccoliC., & YamasakiH. (1993). An improved long-term culture of rat hepatocytes to detect liver tumour-promoting agents: results with phenobarbital. European Journal of Pharmacology248, 59–66.
75.
GouletF., NormandC., & MorinO. (1988). Cellular interactions promote tissue-specific function, biomatrix deposition and functional communication of primary cultured hepatocytes. Hepatology8, 1010–1018.
76.
BegueJ.M., Guguen-GuillouzoC., PasdeloupN., & GuillouzoA. (1984). Prolonged maintenance of active cytochrome P450 in adult rat hepatocytes co-cultured with another liver cell type. Hepatology4, 839–842.
77.
GuillouzoA., MorelF., FardelO., & MeunierB. (1993). Use of human hepatocyte cultures for drug metabolism studies. Toxicology82, 209–219.
78.
DonatoM.T., CastellJ.V., & Gómez-LechónM.J. (1990). Prolonged expression of biotrans-formation activities of rat hepatocytes co-cultured with established cell lines. Toxicology in Vitro4, 461–466.
79.
DonatoM.T., Gómez-LechónM.J., & CastellJ.V. (1990). Drug metabolizing enzymes in rat hepatocytes co-cultured with cell lines. In Vitro Cellular and Developmental Biology — Animal26, 1057–1062.
80.
DonatoM.T., Gómez-LechónM.J., & CastellJ.V. (1991). Rat hepatocytes cultured on a monkey kidney cell line: expression of biotransformation and metabolic activities. Toxicology in Vitro5, 435–438.
81.
DonatoM.T., CastellJ.V., & Gómez-LechónM.J. (1994). Cytochrome P450 activities in pure and co-cultured rat hepatocytes: effects of model inducers. In Vitro Cellular and Developmental Biology — Animal30, 825–832.
82.
TongJ.Z., De LagausieP., FurlanV., CresteilT., BernardO., & AlvarezF. (1992). Long-term culture of adult rat hepatocyte spheroids. Experimental Cell Research200, 326–332.
83.
RobertsR.A., & SoamesA.R. (1993). Hepatocyte spheroids: prolonged hepatocyte viability for in vitro modelling of nongenotoxic carcinogenesis. Fundamental and Applied Toxicology21, 149–158.
84.
LiA.P., ColburnM., & BeckD.J. (1992). A simplified method for the culturing of primary adult rat and human hepatocytes as multicellular spheroids. In Vitro Cellular and Developmental Biology28, 673–677.
85.
YumotoA.U., WatanabeS., HiroseM., KitamuraT., YamaguchiY., & SatoN. (1996). Structural and functional features of bile canaliculi in adult rat hepatocyte spheroids. Liver16, 61–66.
86.
TamuraT., KoideN., HadaH., ShirahaH., & TsujiA. (1995). Gene expression of liver specific proteins in hepatocyte spheroids in primary culture. Acta Medica Okoyama43, 161–167.
87.
WuF.J., FriendJ.R., HsiaoC.C., ZillioxM.J., KoCerraF.B., & HuW. (1996). Efficient assembly of rat hepatocyte spheroids for tissue engineering applications. Biotechnology and Bioengineering50, 404–415.
88.
HamiltonG.A., AtterwillC., WilcoxP., & GeorgeE. (1997). Characterisation of the liver spheroids model for the investigation of hepatotoxicity in vitro. Human and Experimental Toxicology16, 398.
89.
GeorgeE., HamiltonG., & WestmorelandC. (1996). The use of in vitro models in hepatotoxicity testing. Toxicology and Ecotoxicology News3, 142–152.
90.
AmmanP., & MaierP. (1997). Preservation and inducibility of xenobiotic metabolism in long-term cultures of adult rat liver cell aggregates. Toxicology in Vitro11, 45–56.
91.
JuilleratM., MarceauN., CoeytauxS., SierraF., KolodziejezykE., & GuigozY. (1997). Expression of organ specific structures and functions in long-term cultures of aggregates from adult liver cells. Toxicology in Vitro11, 57–69.
92.
NemotoN., SakuraiJ., & FonacY. (1995). Maintenance of phenobarbital-inducible CYP2B gene expression in C52B1/6n mouse hepatocytes in primary culture as spheroids. Archives of Biochemistry and Biophysics316, 362–369.
93.
AbramovitzM., IshigakiS., & ListowskI. (1989). Differential regulation of glutathione S-transferase in cultured hepatocytes. Hepatology9, 235–239.
94.
ReidL.M., FiorinoA.S., SigalS.H., & HolstP.A. (1992). Extracellular matrix gradients in the space of Disse: relevance to liver biology. Hepatology15, 1198–1203.
95.
Ben-Ze'evA., RobinsonG.S., BucherN.L., & FarmerS.R. (1988). Cell–cell and cell–matrix interactions differentially regulate the expression of hepatic and cytoskeletal genes in primary cultures of rat hepatocytes. Proceedings of the National Academy of Sciences, USA85, 2161–2165.
96.
SaadB., SchollF.A., ThomasH., SchawalderH., StreitV., WaechterF., & MaierP. (1993). Crude liver membrane fractions and extracellular matrix components as substrata regulate differentially the preservation and inducibility of cytochrome P450 isoenzymes in cultured rat hepatocytes. European Journal of Biochemistry213, 805–814.
97.
BarnesD. (1984). Attachment factors in cell culture. In The Use of Serum-free and Hormone-supplemented Media (ed. MatherJ.P.), pp. 195–203. New York, USA: Plenum Press.
98.
RojkindM., GatmaitanZ., MacKensenS., GiambroneM.A., PonceP., & ReidL.M. (1980). Connective tissue biomatrix: its isolation and utilization for long-term cultures of normal rat hepatocytes. Journal of Cell Biology87, 255–263.
99.
SilvaJ.M., MorinP.E., DayS.H., KennedyB.P., PayetteP., RushmoreT., YergeyJ.A., & Nicoll-GriffithD.A. (1998). Refinement of an in vitro cell model for cytochrome P450 induction. Drug Metabolism and Disposition26, 490–496.
100.
GuillouzoA. (1992). Hepatotoxicity. In In Vitro Toxicity Testing: Applications to Safety Evaluation (ed. FrazierJ.M.), pp. 45–83. New York, USA: Marcel Dekker.
101.
DunnJ.C.Y., TompkinsR.G., & YarmushM.L. (1991). Long-term culture in a sandwich configuration. FASEB Journal3, 237–245.
102.
DunnJ.C.Y., TompkinsR.G., & YarmushM.L. (1991). Long-term in vitro function of adult hepatocytes in a collagen sandwich configuration. Biotechnology in Progress7, 237–245.
103.
DunnJ.C.Y., YarmushM.L., KoebeH.G., & TompkinsR.G. (1989). Hepatocyte function and extracellular matrix geometry: long-term culture in a sandwich configuration. FASEB Journal3, 174–177.
104.
KernA., BaderA., PichlmayrR., & SewingK.F. (1997). Drug metabolism in hepatocyte sandwich cultures of rats and humans. Biochemical Pharmacology54, 761–772.
105.
De SmetK., CallaertsA., VercruysseA., & RogiersV. (1997). Effect of phenobarbital on 7-ethoxycoumarin-O-deethylase and microsomal epoxide hydrase activities in collagen gel cultures of rat hepatocytes. Toxicology in Vitro11, 459–463.
106.
BaderA., ZechK., CromeO., ChristiansU., RingeB., PichlmayrR., & SewingK.F. (1994). Use of organotypical cultures of primary hepatocytes to analyze drug biotransformation in man and animals. Xenobiotica24, 623–633.
107.
BekenS., TytgatT., PahernikS., KoebeH., VercruysseA, & RogiersV. (1997). Cell morphology, albumin secretion and glutathione S-transferase expression in collagen gel sandwich and immobilization cultures of rat hepatocytes. Toxicology in Vitro11, 409–416.
108.
LeCluyseE., AudusK., & HochmanJ. (1994). Formation of extensive canalicular networks by rat hepatocytes cultured in collagen sandwich configuration. American Journal of Physiology266, 1764–1774.
109.
MichalopoulosG., BowenW., NusslerA., BecichM., & HowardT. (1993). Comparative analysis of mitogenic and morphogenic effects of HGF and EGF on rat and human hepatocytes maintained in collagen gels. Journal of Cellular Physiology156, 443–452.
110.
LeeJ., MorganJ., TompkinsR., & YarmushM. (1993). Proline-mediated enhancement of hepatocyte function in a collagen gel sandwich configuration. Federation of American Societies for Experimental Biology Journal7, 586–591.
111.
De SmetK., CallaertsA., VercruysseA., & RogiersV. (1998). Effect of EGF on ethoxyresorufin O-deethylase activity and DNA synthesis in collagen gel cultures. Experimental and Toxicological Pathology50, 100.
112.
KoebeH., WickM., CramerU., LangeV., & SchildbergF. (1994). Collagen immobilization provides a suitable cell matrix for long-term human hepatocyte cultures in hybrid reactors. The International Journal of Artificial Organs17, 95–106.
113.
KoebeH., PahernikS., EyerP., & SchildbergF. (1994). Collagen gel immobilization: a useful cell culture technique for long-term metabolic studies on human hepatocytes. Xenobiotica24, 95–107.
114.
CurrenR.D., SoutheeJ.A., SpielmannH., LiebschM., FentemJ.F., & BallsM. (1995). The role of prevalidation in the development, validation and acceptance of alternative methods. ATLA23, 211–217.
115.
BallsM., BlaauboerB.J., FentemJ.F., BrunerL., CombesR.D., EkwallB., FielderR.J., GuillouzoA., LewisR.W., LovellD.P., ReinhardtC.A., RepettoG., SladowskiD., SpielmannH., & ZuccoF. (1995). Practical aspects of the validation of toxicity test procedures. ATLA23, 129–147.
116.
FentemJ.H., & BallsM. (1997). The ECVAM approach to validation. In Animal Alternatives, Welfare and Ethics (ed. van ZutphenL.F.M., & BallsM.), pp. 1083–1089. Amsterdam, The Netherlands: Elsevier.
117.
AndersonR., O'HareM., BallsM., BradyM., BrahamsD., BurtA., ChesnéC., CombesR., DenissonA., GarthoffB., HawksworthG., KalterE., LechatA., MayerD., RogiersV., SladowskiD., SoutheeJ., TraffordJ., van der ValkJ., & van ZellerA.M. (1998). The availability of human tissue for biomedical research. The report and recommendations of ECVAM workshop 32. ATLA26, 763–777.
118.
SeglenP.O. (1993). Isolation of hepatocytes by collagenase perfusion. In Methods in Toxicology (ed. TysonC.A., & FrazierJ.M.), pp. 231–243. San Diego, CA, USA: Academic Press.
119.
MatsumotoK., & NakamuraT. (1996). Techniques for the isolation and cultivation of hepatocytes using collagenase. In Cell and Tissue Culture: Laboratory Procedures, Update 4 (ed. DoyleA., GriffithsJ.B., & NewellD.G.), pp. 12B:16.1–12B:16.12. Chichester, West Sussex, UK: John Wiley & Sons.
120.
DebastG., CoeckeS., AkrawiM., ForiersA., VercruysseA., PhillipsI.R., ShephardE.A., & RogiersV. (1995). Effect of EtOH on glutathione S-transferase expression in co-cultured rat hepatocytes. Toxicology in Vitro9, 467–471.
121.
MadanA., DeHaanR., MudraD., CarrollK., LeCluyseE., & ParkinsonA. (1999). Effect of cryopreservation on cytochrome P450 enzyme induction in cultured rat hepatocytes. Drug Metabolism and Disposition27, 327–335.
122.
RuttenA.A., FalkeH.E., CatsburgJ.E., WortelboerH.M., BlaauboerB.J., DoornL., van LeeuwenF.X., TheelenR., & RietjensI.M. (1992). Interlaboratory comparison of microsomal ethoxyresorufin and pentoxyresorufin O-dealkylation determinations: standardization of assay conditions. Archives of Toxicology66, 237–244.
123.
GuyomardC., RiallandL., FremondB., ChesnéC., & GuillouzoA. (1996). Influence of alginate gel entrapment and cryopreservation on survival and xenobiotic metabolism capacity of rat hepatocytes. Toxicology and Applied Pharmacology141, 349–356.
124.
RueggC.E., SilberP.M., MughalR.A., IsmailJ., LuC., BodeD.C., & LiA.P. (1997). Cytochrome P450 induction and conjugated metabolism in primary human hepatocytes after cryopreservation. In Vitro Toxicology10, 217.
125.
Guguen-GuillouzoC., & GuillouzoA. (1983). Modulation of functional activities in cultured rat hepatocytes. Molecular and Cellular Biochemistry53/54, 35–56.
126.
ClementB., Guguen-GuillouzoD., CampionJ.P., GlaiseD., BourelM., & GuillouzoA. (1984). Long-term co-cultures of adult human hepatocytes with rat liver epithelial cells: modulation of albumin secretion and accumulation of extracellular material. Hepatology4, 373–380
127.
GuillouzoA., DelersF., ClementB., BernardN., & EnglerR. (1984). Long-term production of acute-phase proteins by adult rat hepatocytes co-cultured with another liver cell type in serum-free medium. Biochemical and Biophysical Research Communications120, 311–317.
128.
LescoatG., ThezeN., ClementB., GuillouzoA., & Guguen-GuillouzoC. (1985). Modulation of fetal and neonatal rat hepatocyte functional activity by glucocorticoids in co-culture. Cell Differentiation16, 259–268.
129.
LescoatG., PasdeloupN., KneipB., & Guguen-GuillouzoC. (1987). Modulation of α-fetoprotein, albumin and transferrin gene expression by cellular interactions and dexamethasone in co-cultures of fetal rat hepatocytes. European Journal of Cell Biology44, 128–134.
130.
MesnilM., FraslinJ.M., PiccoliC., YamasakiH., & Guguen-GuillouzoC. (1987). Cell contact but not junctional communication (dye coupling) with biliary epithelial cells is required for hepatocytes to maintain differentiated functions. Experimental Cell Research173, 524–533.
131.
ShimaokaS., NakamuraT., & IchiharaA. (1987). Stimulation of growth of primary cultured rat hepatocytes without growth factors by co-culture with non-parenchymal liver cells. Experimental Cell Research172, 228–242.
132.
AgiusL. (1988). Metabolic interactions of parenchymal hepatocytes and dividing epithelial cells in co-culture. Biochemical Journal252, 23–28.
133.
ClementB., LaurentM., Guguen-GuillouzoC., LebeauG., & GuillouzoA. (1988). Types I and IV procollagen gene expression in cultured rat hepaocytes. Collagen Related Research8, 349–359.
134.
ClementB., RescanP.Y., BaffetG., LorealO., LehryD., CampionJ.P., & GuillouzoA. (1988). Hepatocytes may produce laminin in fibrotic liver and in primary culture. Hepatology8, 794–803.
135.
Guguen-GuillouzoC., GriponP., VandenbergheY., LamballeF., RatanasavanhD., & GuillouzoA. (1988). Hepatotoxicity and molecular aspects of hepatocyte function in primary culture. Xenobiotica18, 773–783.
136.
GuillouzoA., BéguéJ.M., MaurerG., & KochP. (1988). Identification of metabolic pathways of pindolol and fluperlapine in adult human hepatocyte cultures. Xenobiotica18, 131–139.
137.
PepinD., ChambazJ., RisselM.Y., GuillouzoA., & BereziatG. (1988). Essential fatty acid pattern of glycerolipids in rat hepatocytes in primary culture and in co-culture with rat liver epithelial cells. Lipids23, 784–790.
138.
CoeckeS., CornetM., VerleyeG., VercruysseA., & RogiersV. (1998). Hormonal regulation of microsomal flavin-containing monooxygenase activity by sex steroids and growth hormone in co-cultured adult male rat hepatocytes. Biochemical Pharmacology56, 1047–1051.
139.
VandenbergheY., RatanasavanhD., GlaiseD., & GuillouzoA. (1988). Influence of various soluble factors on glutathione S-transferase activity in adult rat hepatocytes during culture. In Vitro Cellular and Developmental Biology24, 281–288.
140.
BourelM., GuillouzoA., & Guguen-GuillouzoC. (1989). Drugs and the culturing of hepatocytes. Bulletin de l'Academie Nationale de Medecine173, 409–412.
141.
MorelF., VandenbergheY., PembleS., TaylorJ.B., RatanasavanhD., RogiersV., & KettererB. (1989). Regulation of glutathione S-trans-ferase subunits 3 and 4 in cultured rat hepato-cytes. FEBS Letters258, 99–102.
142.
VandenbergheY., MorelF., ForiersA., KettererB., VercruysseA., GuillouzoA., & RogiersV. (1989). Effect of phenobarbital on the expression of glutathione S-transferase isoenzymes in cultured rat hepatocytes. FEBS Letters251, 59–64.
143.
WestergaardN., SchousboeA., GrunnetN., & DichJ. (1989). Characterization of a co-culture system of neurons and hepatocytes. Neurochemical Research14, 1203–1207.
144.
YamamotoN., ImizatoK., & MasumotoA. (1989). Growth stimulation of adult rat hepatocytes in a primary culture by soluble factor(s) secreted from nonparenchymal liver cell. Cell Structure and Function14, 217–229.
145.
ConnerJ., Vallet-CollomI., DaveauM., DelersF., HironM., LebretonJ.P., & GuillouzoA. (1990). Acute-phase-response induction in rat hepatocytes co-cultured with rat liver epithelial cells. Biochemical Journal266, 683–688.
146.
VandenbergheY., ForiersA., RogiersV., & VercruysseA. (1990). Changes in expression and “de novo” synthesis of glutathione S-trans-ferase subunits in cultured adult rat hepatocytes. Biochemical Pharmacology39, 685–690.
147.
VandenbergheY., MorelF., PembleS., TaylorJ.B., RogiersV., RatanasavanhD., VercruysseA., KettererB., & GuillouzoA. (1990). Changes in expression of mRNA coding for glutathione S-transferase subunits 1, 2 and 7 in cultured rat hepatocytes. Molecular Pharmacology37, 372–376.
148.
BaffetG., LoyerP., GlaiseD., CorluA., EtienneP.L., & Guguen-GuillouzoC. (1991). Distinct effects of cell–cell communication and corticosteroids on the synthesis and distribution of cytokeratins in cultured rat hepatocytes. Journal of Cell Science99, 609–615.
149.
De La VegaF.M., & Mendoza-FigueroaT. (1991). Effects of probucol on lipid metabolism and secretion in long-term cultures of adult rat hepatocytes. Biochimica et Biophysica Acta1081, 293–300.
150.
MertensK., RogiersV., SonckW., & VercruysseA. (1991). Reduced and oxidized glutathione contents in adult rat hepatocytes under various culture conditions. Cell Biology and Toxicology7, 101–110.
151.
NiemannC., GauthierJ.C., RichertL., IvanovM.A., MelcionC., & CordierA. (1991). Rat adult hepatocytes in primary and pure mixed monolayer culture: comparison of the maintenance of mixed function oxidase and conjugation pathways of drug metabolism. Biochemical Pharmacology42, 373–379.
152.
UteschD., MolitorE., PlattK.L., & OeschF. (1991). Differential stabilization of cytochrome P450 isoenzymes in primary cultures of adult rat liver parenchymal cells. In Vitro Cellular and Developmental Biology27, 858–863.
153.
VandenbergheY., TeeL., MorelF., RogiersV., GuillouzoA., & YeohG. (1991). Regulation of glutathione S-transferase gene expression by phenobarbital in cultured adult rat hepatocytes. FEBS Letters284, 103–108.
154.
VossJ.U., & SeibertH. (1991). Microcarrier-attached rat hepatocytes as a xenobiotic-metabolizing system in co-cultures. Cell Biology and Toxicology7, 387–399.
155.
UteschD., & OeschF. (1992). Dependency of the in vitro stabilization of differentiated functions in liver parenchymal cells on the type of cell line used for co-culture. In Vitro Cellular and Developmental Biology28, 190–198.
156.
VandenbergheY., TeeL., RogiersV., & YeohG. (1992). Transcriptional- and post-transcriptional-dependent regulation of glutathione S-transferase expression in rat hepatocytes as a function of culture conditions. FEBS Letters313, 155–159.
157.
WegnerH., SchareckW., Bayer-HelmsH., & GebhardtR. (1992). Different proliferative potential of rat and pig hepatocytes in pure primary culture and co-culture. European Journal of Cell Biology58, 411–417.
158.
AkrawiM., RogiersV., VandenbergheY., PalmerC.N., VercruysseA., ShephardE.A., & PhillipsI.R. (1993). Maintenance and induction in co-cultured rat hepatocytes of components of the cytochrome P450-mediated mono-oxygenase. Biochemical Pharmacology45, 1583–1591.
159.
AkrawiM., ShephardE.A., PhillipsI.R., VercruysseA., & RogiersV. (1993). Effects of phenobarbital and valproate on the expression of cytochrome P450 mediated mono-oxygenases in co-cultured rat hepatocytes. Toxicology in Vitro7, 477–480.
160.
CoeckeS., SegaertA., VercruysseA., & RogiersV. (1993). Expression of flavin-containing mono-oxygenase activity in adult rat hepatocytes under various culture conditions. Toxicology In Vitro7, 481–487.
161.
HernandezA., LópezM.L., ChamorroG., & Mendoza-FigueroaT. (1993). Inhibition of lipid synthesis and secretion in long-term cultures of adult rat hepatocytes by α-asarone. Planta Medica59, 121–124.
162.
LorealO., LevavasseurF., FromagetS., GrosD., GuillouzoA., & ClementB. (1993). Cooperation of Ito cells and hepatocytes in the deposition of an extracellular matrix in vitro. American Journal of Pathology143, 538–544.
163.
MertensK., RogiersV., & VercruysseA. (1993). Glutathione dependent detoxication in adult rat hepatocytes under various culture conditions. Archives of Toxicology67, 680–685.
164.
MertensK., RogiersV., & VercruysseA. (1993). Measurement of malondialdehyde in cultures of adult rat hepatocytes. Toxicology in Vitro7, 439–441.
165.
RescanP.Y., LorealO., HassellJ.R., YamadaY., GuillouzoA., & ClementB. (1993). Distribution and origin of the basement membrane component perlecan in rat liver and primary hepatocyte culture. American Journal of Pathology142, 199–208.
166.
RogiersV., & VercruysseA. (1993). Rat hepatocyte cultures and co-cultures in biotransformation studies of xenobiotics. Toxicology82, 193–208.
167.
DienerB., BeckerR., MartusH.J., TraiserM., SteinbergP., & OeschF. (1995). Malignantly transformed non-parenchymal liver epithelial cells and transformed oval cells suppress the homotypical gap junctional intercellular communication of co-cultured rat liver parenchymal cells. Carcinogenesis16, 633–636.
168.
Jurima-RometM., CasleyW.L., NeuJ.M., & HuangH.S. (1995). Induction of CYP3A and associated terfenadine N-dealkylation in rat hepatocytes co-cultured with 3T3 cells. Cellular Biology and Toxicology11, 313–327.
169.
OeschF., & DienerB. (1995). Cell systems for use in studies on the relationship between foreign compound metabolism and toxicity. Pharmacology and Toxicology76, 325–327.
170.
Quintanilla-VegaB., HernádezA., LópezM.L., García VargasG., CebriánM.E., & Men-doza FigueroaT. (1995). Porphyrin production and excretion by long-term cultures of adult rat hepatocytes and effect of lead exposure. Toxicology102, 275–283.
171.
RojkindM., NovikoffP.M., GreenwelP., RubinJ., Rojas-ValenciaL., de CarvalhoA.C., StockertR., SprayD., HertzbergE.L., & WolkoffA.W. (1995). Characterization and functional studies on rat liver fat-storing cell line and freshly isolated hepatocyte co-culture system. American Journal of Pathology146, 1508–1520.
172.
RogiersV., VandenbergheY., CallaertsA., SonckW., & VercruysseA. (1990). Effects of dimethylsulphoxide on Phase I and II biotransformation in cultured rat hepatocytes. Toxicology in Vitro4, 439–442.
173.
TraiserM., DienerB., UteschD., & OeschF. (1995). The gap junctional intercellular communication is no prerequisite for the stabilization of xenobiotic metabolizing enzyme activities in primary rat liver parenchymal cells in vitro. In Vitro Cellular and Developmental Biology31, 266–273.
174.
KoikeM., MatsushitaM., TaguchiK., & UchinoJ. (1996). Function of culturing mono-layer hepatocytes by collagen gel coating and co-culture with non-parenchymal cells. Artificial Organs20, 186–192.
LiuL., LeCluyseE., LiuJ., & KlaassenC. (1996). Sulfotransferase gene expression in primary cultures of rat hepatocytes. Biochemical Pharmacology52, 1621–1630.
177.
MertensK., KaufmanS., WaterschootS., VercruysseA., & RogiersV. (1996). Effect of tertiary butylhydroperoxide-induced oxidative stress on glutathione content and thiobarbituric acid reactive substances production in cultures and co-cultures of adult rat hepatocytes. Toxicology in Vitro10, 507–511.
178.
RenP., & RuchR.J. (1996). Inhibition of gap junctional intercellular communication by barbiturates in long-term primary cultured rat hepatocytes is correlated with liver tumour promoting activity. Carcinogenesis17, 2119–2124.
179.
CorluA., IlyinG., CariouS., LamyI., LoyerP., & Guguen-GuillouzoC. (1997). The co-culture: a system for studying the regulation of liver differentiation/proliferation activity and its control. Cell Biology and Toxicology13, 235–242.
180.
FautrelA., JolyB., GuyomardC., & GuillouzoA. (1997). Long-term maintenance of drug-metabolizing enzyme activities in rat hepatocytes after cryopreservation. Toxicology and Applied Pharmacology147, 110–114.
181.
KonoY., YangS., & RobertsE. (1997). Extended primary culture of human hepatocytes in a collagen gel sandwich system. In Vitro Cellular and Developmental Biology — Animal33, 467–472.
182.
LercheC., FautrelA., ShawP.M., GlaiseD., BalletF., GuillouzoA., & CorcosL. (1997). Regulation of the major detoxication functions by phenobarbital and 3-methylcholanthrene in co-cultures of rat hepoatocytes and liver epithelial cells. European Journal of Biochemistry244, 98–106.
183.
VanhaeckeT., De SmetK., BekenS., PauwelsM., VercruysseA., & RogiersV. (1998). Rat hepatocyte cultures: conventional cultures and co-cultures with rat liver epithelial cells. In Cytochrome P450 Protocols. Series in Methods in Molecular Biology (ed. PhillipsI., & Shep-hardE.), pp. 103–110. Totowa, NJ, USA: Humana Press.
LandryJ., BernierD., OuelletC., GayetteR., & MarceauN. (1985). Spheroidal aggregate culture of rat liver cells: histotypic reorganisation biomatrix deposition and maintenance of functional activities. Journal of Cell Biology101, 914–924.
186.
GuigozY., WerffeliP., FavreD., JuilleratM., WellingerR., & HoneggerP. (1987). Aggregate cultures of foetal rat liver cells: development and maintenance of liver gene expression. Biologie Cellulaire60, 163–171.
187.
KoideN., ShinjiT., TanabeT., AsanoK., KawaguchiM., SakaguchiK., KoideY., MoriM., & TsujiT. (1989). Continued high albumin production by multicellular spheroids of adult rat hepatocytes formed in the presence of liver-derived proteoglycans. Biochemical and Biophysical Research Communications161, 385–391.
188.
TakezawaT., YamazakiM., MoriY., YonahaT., & YoshizatoK. (1992). Morphological and immuno-cytochemical characterisation of a hetero spheroid composed of fibroblasts and hepatocytes. Journal of Cell Science101, 495–501.
189.
UenoK., MiyashitaA., EndohK., TakezawaT., YamazakiM., MoriY., & SatohT. (1992). Formation of multicellular spheroids composed of rat hepatocytes. Research Communications in Chemical Pathology and Pharmacology77, 107–120.
190.
EndohK., VerpK., MiyashitoA., & SatohT. (1993). Size regulation and biochemical activities of the multicellular spheroid composed of rat liver cells. Research Communications in Chemical Pathology and Pharmacology83, 317–327.
191.
TongJ.Z., SarrazinS., CassioD., GauthierF., & AlvarezF. (1994). Application of spheroid culture to human hepatocytes and maintenance of their differentiation. Biologie Cellulaire81, 77–81.
192.
LazarA., PeshwaM.V., WuF.J., ChiC.M., CerraF.B., & HuW.S. (1995). Formation of porcine hepatocyte spheroids for use in bioartificial liver. Cell Transplantation4, 259–268.
193.
PeshwaM.W., WuF.J., SharpH.L., CerraF.B., & HuW. (1996). Mechanistics of formation and ultrastructural evaluation of hepatocyte spheroids. In Vitro Cellular and Developmental Biology32, 197–203.
194.
SakaiY., NaruseK., NagashimaI., MutoT., & SuzukiM. (1996). Large scale preparation and function of porcine hepatocyte spheroids. The International Journal of Artificial Organs19, 294–301.
195.
BattleT., MaguireT., MoulsdaleH., & DoyleA. (1999). Progressive maturation resistance to microcystin-LR cytotoxicity in two different hepatospheroidal modelsCell Biology and Toxicology15, 3–12.
196.
YamaguchiS., MurataY., NagayaT., HayashiY., OhmoS., NimuraY., & SeoH. (1999). Glucocorticoids increase retinoid-X receptor α (RXRα) expression and enhance thyroid hormone action in primary cultured rat hepatocytes. Journal of Molecular Endocrinology22, 81–90.
197.
DilworthC., HamiltonG.A., GeorgeE., & Tim-brellJ.A. (1999). The use of liver spheroids as an in vitro model for studying induction of the stress reponse as a marker of chemical toxicity. Toxicology in Vitro, in press.
198.
BaderA., RinkesI., ClossE., RyanC., TonerM., CunninghamJ., TompkinsR., & YarmushM. (1992). A stable long-term hepatocyte culture system for studies of physiological processes: cytokine stimulation of the acute phase response in rat and human hepatocytes. Biotechnology Progress8, 219–225.
199.
Borel-RinkesI., TonerM., EzzellR., Tomp-kinsR., & YarmushM. (1992). Effects of dimethyl sulfoxide on cultured rat hepatocytes in sandwich configuration. Cryobiology29, 443–453.
200.
DunnJ.C.Y., TompkinsR.G., & YarmushM.L. (1992). Hepatocytes in a collagen sandwich: evidence for transcriptional and translational regulation. Journal of Cell Biology116, 1043–1053.
201.
LeeJ., MorganJ., & TompkinsR. (1992). The importance of proline on long-term hepatocyte function in a collagen gel sandwich configuration: regulation of protein secretion. Biotechnology and Bioengeneering40, 298–305.
202.
EzzellR., TonerM., HendricksK., DunnJ., TompkinsR., & YarmushM. (1993). Effect of collagen gel configuration on the cytoskeleton in cultured rat hepatocytes. Experimental Cell Research208, 442–452.
203.
LeeJ., MorganJ.R., TompkinsR.G., & YarmushM.L. (1993). Proline-mediated enhancement of hepatocyte function in a collagen gel sandwich culture configuration. FASEB Journal7, 586–591.
204.
RyanC., CarterE., JenkinsR., SterlingL., YarmushM., MaltR., & TompkinsR. (1993). Isolation and long-term culture of human hepatocytes. Surgery113, 48–54.
205.
KnopE., BaderA., BökerK., PichlmayerR., & SewingK. (1995). Ultrastructural and functional differentiation of hepatocytes under long-term culture conditions. The Anatomical Record242, 337–349.
206.
KonoY., YangS., LetarteM., & RobertsE. (1995). Establishment of a human hepatocyte line derived from primary culture in a collagen gel sandwich culture system. Experimental Cell Research221, 478–485.
207.
RotemA., MatthewH., HsiaoP., TonerM., TompkinsR., & YarmushM. (1995). The activity of cytochrome P4501A1 in stable cultured rat hepatocytes. Toxicology in Vitro9, 139–149.
208.
BaderA., KnopE., KernA., BökerK., FrühaufN., CromeO., EsselmannH., PapeC., KempkaG., & SewingK.F. (1996). 3-D Co-culture of hepatic sinusoidal cells with primary hepatocytes: design of an organotypic model. Experimental Cell Research226, 223–233.
209.
BerthiaumeF., MogheP., TonerM., & YarmushM. (1996). Effect of extracellular matrix topology on cell structure, function and physiological responsiveness: hepatocytes cultured in a sandwich configuration. Federation of American Societies for Experimental Biology Journal10, 1471–1484.
210.
KonoY., & RobertsE. (1996). Modulation of the expression of liver-specific functions in a novel human hepatocyte line cultured in a collagen gel sandwich configuration. Biochemical and Biophysical Research Communications220, 628–632.
211.
MogheP.V., BerthiaumeF., EzzellR.M., TonerM., TompkinsR.G., & YarmushM.L. (1996). Culture matrix configuration and composition in the maintenance of hepatocyte polarity and function. Biomaterials17, 373–385.
212.
BekenS., TytgatT., PahernikS., KoebeH., VercruysseA., & RogiersV. (1997). Cell morphology, albumin secretion and glutathione S-transferase expression in collagen gel sandwich and immobilization cultures of rat hepatocytes. Toxicology in Vitro11, 409–416.
213.
MogheP.V., CogerR., TonerM., & YarmushM.L. (1997). Cell–cell interactions are essential for maintenance of hepatocyte function in collagen gel but not on Matrigel. Biotechnology and Bioengeneering56, 706–711.
214.
PangJ., ZaleskiJ., & KauffmanF. (1997). Toxicity of allyl alcohol in primary cultures of freshly isolated and cryopreserved hepatocytes maintained on hydrated collagen gels. Toxicology and Applied Pharmacology142, 87–94.
215.
TalaminiM., KappusB., & HubbardA. (1997). Repolarization of hepatocytes in culture. Hepatology25, 167–172.
216.
Parsons-WingerterP., & SaltzmanW. (1993). Growth versus function in the three-dimensional culture of single and aggregated hepatocytes within collagen gels. Biotechnology Progress9, 600–607.
217.
SaltzmanW., ParkhurstM., Parsons-WingerterP., & ZhuW. (1992). Three-dimensional cell cultures mimic tissues. Annals of the New York Academy of Sciences665, 259–273.
218.
PahernikS., SchmidtJ., SauterT., Schild-bergF., & KoebeH.G. (1995). Metabolism of pimobendan in long-term human hepatocyte culture: in vivo–in vitro comparison. Xenobiotica25, 811–823.
219.
NishikawaY., TokusashiY., KadohamaT., NishimoriH., & OgawaK. (1996). Hepatocytic cells form bile-duct like structures within a three-dimensional collagen gel matrix. Experimental Cell Research223, 357–371.
220.
PahernikS., ThaslerW., Mueller-HoeckerJ., SchildbergF., & KoebeH. (1996). Hypothermic storage of pig hepatocytes: influence of different storage solutions and cell density. Cryobiology33, 552–566.
221.
WickM., KoebeH., & SchildbergF. (1996). Extracorporeal artificial liver: the influence of a second cell layer on the morphology and function of immobilized human hepatocytes. The International Journal of Artificial Organs19, 415–421.
222.
Gómez-LechónM.J., JoverR., DonatoT., PonsodaX., RodriguezC., StenzelK.G., KlockeR., PaulD., GuillenI., BortR., & CastellJ.V. (1998). Long-term expression of differentiated functions in hepatocytes cultured in the three-dimensional collagen matrix. Journal of Cell Physiology177, 553–562.
223.
DoehmerJ., WolfelC., DofraS., DoehmerC., SeidelA., GlattK.L., OeschF., & GlattH.R. (1992). Applications of stable V79-derived cell lines expressing rat cytochromes P450 1A1, 1A2 and 2B1. Xenobiotica22, 1093–1099.
224.
EkinsS., RingB.J., BinkleyS.N., HallS.D., & WrightonS.A. (1998). Autoactivation and activation of the cytochromes P450. International Journal of Clinical Pharmacology36, 642–651.
225.
KennedyS.W., LorenzenA., JamesC.A., & CollinsB.T. (1993). Ethoxyresorufin-O-deethy-lase and porphyrin analysis in chicken embryo hepatocyte cultures with a fluorescence multi-well plate reader. Analytical Biochemistry211, 102–112.
226.
BerthouF., FlinoisJ.P., RatanasavanhD., BeauneP., RicheC., & GuillouzoA. (1989). Comparison of caffeine metabolism by slices, microsomes and hepatocyte cultures from adult human liver. Xenobiotica19, 401–417.
227.
CrespiC.L. (1999). Higher-throughput screening with human cytochromes P450. Current Opinion in Drug Discovery2, 15–19.
228.
DistlerathL.M., ReillyP.E.B., MartinM.V., DavisG.G., WilkinsonG.R., & GuengerichF.P. (1985). Purification and characterisation of the human liver cytochrome P450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. Journal of Biological Chemistry260, 9057–9067.
229.
McKillopD., WildM.J., ButtersC.J., & Sim-cockC. (1998). Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica28, 845–853.
230.
ShimadaT., MimuraM., InoueK., NakamuraS., OdaH., OhmuriS., & YamazakiH. (1997). Cytochrome P450-dependent drug oxidation activities in liver microsomes of various animal species including rats, guinea-pigs, dogs, monkeys and humans. Archives of Toxicology71, 401–408.
231.
ButlerM.A., IwasakiM., GuengerichF.P., & KadlubarF.K. (1989). Human cytochrome P450PA (P4501A2), the phenacetin-O-deethy-lase is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proceedings of the National Acadamy of Science, USA86, 7696–7700.
232.
ChungW.G., RohH.K., KimH.M., & ChaY.N. (1998). Involvement of CYP3A1, 2B1 and 2E1 in C-8 hydroxylation and CYP1A2 and flavin-containing monooxygenases in N-demethylation of caffeine: identified by using inducer treated rat liver microsomes that are characterised with testosterone metabolic patterns. Chemico-Biological Interactions113, 1–14.
233.
MonshouwerM., van't KloosterG.A.E., NijmeijerS.M., WitkampR.F., & van MiertA.S.P.A.M. (1998). Characterization of cytochrome P450 isoenzymes in primary cultures of pig hepatocytes. Toxicology in Vitro12, 715–723.
234.
BrosenK., SkjelboE., & NielsenK.K. (1996). Imipramine: a model for P450 research. Methods in Enzymology272, 177–186.
235.
BullS., CatalaniP., GarleM., CoeckeS., & ClothierR. (1999). Imipramine for cytochrome P450 activity determination: a multiple-species metabolic probe. Toxicology in Vitro, in press.
236.
MinersJ.O., CoulterS., TukeyR.H., VeroneseM.E., & BirkettD.J. (1996). Cytochrome P450, 1A2 and 2C9 are responsible for the human hepatic O-demethylation of R- and S-naproxen. Biochemical Pharmacology51, 1003–1008.
237.
YamazakiH., TanakaM., & ShimadaT. (1999). Highly sensitive high-performance liquid chromatographic assay for coumarin 7-hydroxylation and 7-ethoxycoumarin O-deethylation by human liver cytochrome P450 enzymes. Journal of Chromatography B: Biomedical Applications721, 13–19.
238.
YamazakiH., MimuraM., SugaharaC., & ShimadaT. (1994). Catalytic roles of rat and human cytochrome P4502A in testosterone 7-α- and coumarin 7-hydroxylation. Biochemical Pharmacology48, 1524–1527.
239.
YunC.H., ShimadaT., & GuengerichF.P. (1991). Purification and characterisation of human liver microsomal cytochrome P4502A6. Molecular Pharmacology40, 679–685.
240.
PatersonP., FryJ.R., & HornerS.A. (1984). Influence of cytochrome P450 type on the pattern of conjugation of 7-hydroxycoumarin generated from 7-alkoxycoumarins. Xenobiotica14, 849–859.
241.
YamanoS., TatsunoJ., & GonzalezF.J. (1990). The CYP2A3 gene product catalyses coumarin 7-hydroxylation in human liver microsomes. Biochemistry29, 1322–1329.
242.
ChangT.K., WeberG.F., CrespiC.L., & WaxenD.J. (1993). Differential activation of cyclophosphamide and ifosphamide by cytochromes P4502B and 3A in human liver microsomes. Cancer Research53, 5629–5637.
243.
DoehmerJ., SeidelA., OeschF., & GlattH.R. (1990). Genetically engineered V79 Chinese hamster cells metabolically activate the cytostatic drugs cyclophosphamide and ifos-famide. Environmental Health Perspectives88, 63–65.
244.
YuL.J., DrewesP., GustafssonK., BrainE.G., HechtJ.E., & WaxmanD.J. (1999). In vivo modulation of alternative pathways of P450-catalyzed cyclophosphamide metabolism: impact on pharmacokinetics and antitumour activity. Journal of Pharmacology and Experimental Therapeutics288, 928–937.
245.
DonatoM.T., Gómez-LechónM.J., JoverR., NakamuraT., & CastellJ.V. (1998). Human hepatocytes growth factor down-regulates the expression of cytochrome P450 isozymes in human hepatocytes in primary culture. Journal of Pharmacology and Experimental Therapuetics284, 760–767.
246.
CodeE.L., CrespiC.L., PenmanB.W., GonzalezF.J., ChangT.K.H., & WaxmanD.J. (1997). Human cytochrome P4502B6: interindividual hepatic expression, substrate specificity and role of procarcinogen activation. Drug Metabolism and Disposition25, 985–993.
247.
MorseM.A., & LuJ. (1998). High-performance liquid chromatographic method for measurement of cytochrome P450-mediated metabolism of 7-ethoxy-4-trifluoromethyl-coumarin. Journal of Chromatography B: Bio-medical Applications708, 290–293.
248.
ChangT.K., YuL., MaurelP., & WaxmanD.J. (1997). Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocytes cultures: response to cytochrome P450 inducers and autoinduction by oxazaphosphorines. Cancer Research57, 1946–1954.
249.
RahmanA., KorzekwaK.R., GroganJ., GonzalezF.J., & HarrisJ.W. (1994). Selective bio-transformation of taxol to 6α-hydroxytaxol by human cytochrome P4502C8. Cancer Research54, 5543–5546.
250.
KostrubskyV.E., LewisL.D., WoodS.G., SinclairP.R., WrightonS.A., & SinclairJ.F. (1997). Effect of taxol on cytochrome P4503A and acetaminophen toxicity in cultured rat hepatocytes: comparison to dexamethazone. Toxicology and Applied Pharmacology142, 79–86.
251.
KostrubskyV.E., LewisL.D., StromS.C., WoodS.G., SchuetzE.G., SchuetzJ.D., SinclairP.R., WrightonS.A., & SinclairJ.F. (1998). Induction of cytochrome P4503A by taxol in primary cultures of human hepatocytes. Archives of Biochemistry and Biophysics355, 131–136.
252.
EngelG., HofmannU., HeidemannH., CosmeJ., & EichelbaumM. (1996). Antipyrine as a probe for human oxidative drug metabolism: identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylan-tipyrine, and norantipyrine formation. Clinical Pharmacology and Therapeutics59, 613–623.
253.
LeemannT., TransonC., & DayerP. (1993). Cytochrome P450TB(CYP2C9): a major monooxygenase catalysing diclofenac 4'-hydroxylation in human liver. Life Sciences52, 29–34.
254.
TangW., StearnsR.A., BandieraS.M., ZhangY., RaabC., BraunM.P., DeanD.C., PangJ., LeungK.H., DossG.A., SraussJ.R., KweiG.Y., RushmoreT.H., ChiuS.H., & BaillieT.A. (1999). Studies on cytochrome P450-mediated bioactivation of diclofenac in rats and in human hepatocytes: identification of glutathione conjugated metabolites. Drug Metabolism and Disposition27, 365–372.
255.
MinersJ.O., & BirkettD.J. (1996). Use of tolbutamide as a substrate probe for human hepatic cytochrome P4502C9. Methods in Enzymology272, 139–145.
256.
LangD., & BockerR. (1995). Highly sensitive and specific high performace liquid chromatographic analysis of 7-hydroxywarfarin, a marker for human P450. Journal of Chromatography672, 305–309.
257.
WrightonS.A., StevensJ.C., BeckerG.W., & VandenbrandenM. (1993). Isolation and characterisation of human liver cytochrome P450 2C19: correlation between 2C19 and S-mephenytoin 4'-hydroxylation. Archives of Biochemistry and Biophysics306, 240–245.
258.
TracyT.S., MarraC., WrightonS.A., GonzalezF.J., & KorzekwaK.R. (1997). Involvement of multiple cytochrome P450 isoforms in naproxen O-demethylation. European Journal of Clinical Pharmacology52, 293–298.
259.
AndersonM.D., BandieraS.M., ChangT.K.H., & BellwardG.D. (1998). Drug effect of androgen administration during puberty on hepatic CYP2C11, CYP3A, and CYP2A1 expression in adult female rats. Drug Metabolism and Disposition26, 1031–1038.
260.
BiaginiC.P., PhilpotR.M., & CelierC.M. (1999). Nonsubstrate recognition site residues are involved in testosterone hydroxylation by cytochrome P450 CYP 2C11. Archives of Biochemistry and Biophysics361, 309–314.
261.
GoldsteinJ.A., FalettoM.B., Romkes-SparkesM., SulivanT., KitareewanS., RaucyJ.L., LaskerJ.M., & GhanayemB.I. (1994). Evidence that CYP2C19 is the major (S)-mephenytoin 4'-hydroxylase in humans. Biochemistry33, 1743–1752.
262.
HickmanD., WangJ.P., WangY., & UnadkatJ.D. (1998). Evaluation of the selectivity of in vitro probes and suitability of organic solvents for the measurement of human cytochrome P450 monooxygenase actvities. Drug Metabolism and Disposition26, 207–215.
263.
DayerP., LeemannT., & StriberniR. (1989). Dextromethorphan O-demethylation in liver microsomes as a prototype reaction to monitor cytochrome P450 dbl activity. Clinical Pharmacology and Therapeutics45, 34–40.
264.
KronbachT. (1991). Bufuralol, dextromethorphan and debrisoquine as pro-type substrates for human P450IID6. Methods in Enzymology206, 509–517.
CrespiC.L., SteimelD.T., PenmanB.W., KorzekwaK.R., FernandezsalgueroP., ButersJ.T.M., GelboinH.V., GonzalezF.J., IdleJ.R., & DalyA.K. (1995). Comparison of substrate metabolism by wild-type CYP2D6 protein and a variant containing methionine, not valine, at position-374. Pharmacogenetics5, 234–243.
267.
YooJ.S., GuengerichF.P., & YangC.S. (1988). Metabolism of N-nitrosodialkylamines by human liver microsomes. Cancer Research48, 1499–1504.
268.
YooJ.S., IshizakiH., & YangG.S. (1991). Enzyme kinetics of N-nitrosodimethylamine demethylase in rodents and humans. IARC Science Publication, 366–369.
269.
WrightonS.A., ThomasP.E., RyanD.E., & LevinW. (1987). Purification and characterization of ethanol-inducible human hepatic cytochrome P450HLj. Archives of Biochemistry and Biophysics258, 292–297.
270.
TassaneeyakulW., VeroneseM.E., BirkettD.J., GonzalezF.J., & MinersJ.O. (1993). Validation of 4-nitrophenol as an in vitro substrate probe for human liver CYP2E1 using cDNA expression and microsomal kinetic techniques. Biochemical Pharmacology46, 1975–1981.
271.
LucasD., MenezJ.F., & BerthouF. (1996). Chlorzoxazone: an in vitro and in vivo substrate probe for liver CYP2E1. Methods in Enzymology272, 115–123.
272.
PeterR., BockerR., BeaubeP.H., IwasakiM., GuengerichF.P., & YangC. (1990). Hydroxylation of chlorzoxazone as a specific probe for human liver P450IIE1. Chemical Research in Toxicology3, 566–573.
273.
YamazakiH., GuoZ., & GuengerichF.P. (1995). Selectivity of cytochrome P4502E1 in chlorzoxazone 6-hydroxylation. Drug Metabolism and Disposition23, 438–440.
274.
AmetY., BerthouF., BairdS., DreamoY., BailJ.P., & MenezJ.F. (1992). Validation of the (omega-1)-hydroxylation of lauric acid as an in vitro substrate probe for human liver CYP2E1. Biochemical Pharmacology50, 1775–1782.
275.
AmetY., LucasD., Zhang-GouillonZ.Q., & FrenchS.W. (1998). P450-dependent metabolism of lauric acid in alcoholic liver disease: comparison between rat liver and kidney microsomes. Alcoholism, Clinical and Experimental Research22, 455–462.
276.
de GroeneE.M., SeinenW., & HorbachG.J. (1995). A NIH/3T3 cell line stably expressing human cytochrome P450-3A4 used in combination with a lacZ’ shuttle vector to study mutagenicity. European Journal of Pharmacology: Environmental Toxicology and Pharmacology293, 47–53.
277.
WaxmanD.L., LapensonD.P., AoyamaT., GelboinH.V., GonzalezF.J., & KorzekwaK. (1991). Steroid hormone hydroxylase specificities of eleven cDNA-expressed cytochromes P450. Archives of Biochemistry and Biophysics290, 160–166.
278.
RenS., YangJ.S., KalhornT.F., & SlatteryJ.T. (1997). Oxidation of cyclophosphamide to 4-hydroxycyclophosphamide in human liver microsomes. Cancer Research57, 4229–4235.
279.
TangW., StearnsR.A., WangR.W., ChiuS.H., & BaillieT.A. (1999). Roles of human hepatic cytochromes P450 2C9 and 3A4 in the metabolic activation of diclofenac. Chemical Research in Toxicology12, 192–199.
280.
ClarkeS.E., BaldwinS.J., BloomerJ.C., Ayr-tonA.D., SozioR.S., & CheneryR.J. (1994). Lauric acid as a model substrate for the simultaneous determination of cytochrome P4502E1 and 4A in hepatic microsomes. Chemical Research in Toxicology7, 836–842.
281.
IerselM.L., PloemenJ.P., StruikI., van AmersfoortC., KeyzerA.E., SchefferlieJ.G., & van BladerenP.J. (1996). Inhibition of glutathione S-transferase activity in human melanoma cells by α,β-unsaturated carbonyl derivatives: effects of acrolein, cinnamaldehyde, citral, crotonaldehyde, curcumin, ethacrynic acid, and trans-2-hexenal. Chemico-Biological Interactions102, 117–132.
282.
TakamatsuY., & InabaT. (1994). Inter-individual variability of human hepatic glutathione S-transferase isozymes assessed by inhibitory capacity. Toxicology88, 191–200.
283.
SalinasA.E. (1999). Glutathione S-transferases: a review. Current Medicinal Chemistry6, 279–309.
284.
RossjohnJ., McKinstryW.J., OakleyA.J., VergerD., FlanaganJ., ChelvanayagamG., TanK.L., BoardP.G., & ParkerM.W. (1998). Human theta class glutathione transferase: the crystal structure reveals a sulfate-binding pocket within a buried active site. Structure6, 309–322.
285.
BoardP.G., BakerR.T., ChelvanayagamG., & JermiinL.S. (1997). Zeta, a novel class of glutathione transferases in a range of species from plants to humans. Biochemical Journal328, 929–935.
286.
FoldesA., & MeekJ.L. (1973). Rat brain phenolsulfotransferase: partial purification and some properties. Biochimica et Biophysica Acta327, 365–374.
287.
RaftogianisR.B., WoodT.C., OtternessD.M., Van LoonJ.A., & WeinshilboumR.M. (1997). Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotype. Biochemical and Biophysical Research Communications239, 298–304.
288.
HommaH., TadaM., NakamuraT., YamagataS., & MatsuiM. (1997). Heterogeneous zonal distribution of sulfotransferase isoenzymes in rat liver. Archives of Biochemistry and Biophysics339, 235–241.
289.
OddyE.A., MancheeG.R., FreemanN.M., WardM.A., & CoughtrieM.W. (1997). Purification and characterization of a canine liver phenol sulfotransferase. Drug Metabolism and Disposition25, 1205–1210.
290.
DajaniR., HoodA.M., & CoughtrieM.W. (1998). A single amino acid, glu146, governs the substrate specificity of a human dopamine sulfotransferase, SULT1A3. Molecular Pharmacology54, 942–948.
291.
DajaniR., SharpS., GrahamS., BethellS.S., CookeR.M., JamiesonD.J., & CoughtrieM.W. (1999). Kinetic properties of human dopamine sulfotransferase (SULT1A3) expressed in prokaryotic and eukaryotic systems: comparison with the recombinant enzyme purified from Escherichia coli. Protein Expression and Purification16, 11–18.
292.
CruickshankD., SansomL.N., VeroneseM.E., MojarrabiB., McManusM.E., & ZhuX. (1993). cDNA expression studies of rat liver aryl sulphotransferase. Biochemical and Biophysical Research Communications191, 295–301.
293.
WangJ., FalanyJ.L., & FalanyC.N. (1998). Expression and characterization of a novel thyroid hormone-sulfating form of cytosolic sulfotransferase from human liver. Molecular Pharmacology53, 274–282.
294.
BurchellB., BrierleyC.H., & RanceD. (1995). Specificity of human UDP-glucurono-syltransferases and xenobiotic glucuronidation. Life Sciences57, 1819–1831.
295.
SingerS.S., & SylvesterS. (1976). Enzymatic sulfation of steroids. II. The control of the hepatic cortisol sulfotransferase activity and of the individual hepatic steroid sulfotrans-ferases of rats by gonads and gonadal hormones. Endocrinology99, 1346–1352.
296.
HillerA., NguyenN., StrassburgC.P., LiQ., JaintaH., PechsteinB., RuusP., EngelJ., TukeyR.H., & KronbachT. (1999). Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Drug Metabolism and Disposition27, 605–612.
297.
BruckM., LiQ., LambJ.G., & TukeyR.H. (1997). Characterization of rabbit UDP-glucuronosyltransferase UGT1A7: tertiary amine glucuronidation is catalyzed by UGT1A7 and UGT1A4. Archives of Biochemistry and Biophysics348, 357–364.
298.
AbidA., BouchonI., SiestG., & SabolovicN. (1995). Glucuronidation in the Caco-2 human intestinal cell line: induction of UDP-glucuronosyltransferase 1*6. Biochemical Pharmacology50, 557–561.
299.
AbidA., SabolovicN., & MagdalouJ. (1997). Expression and inducibility of UDP-glu-curonosyltransferases 1-naphthol in human cultured hepatocytes and hepatocarcinoma cell lines. Life Sciences60, 1943–1951.
300.
Le GuellecC., LacarelleB., VillardP.H., PointH., CatalinJ., & DurandA. (1995). Glucuronidation of propofol in microsomal fractions from various tissues and species including humans: effect of different drugs. Anesthetics and Analgesics81, 855–861.
301.
PillotT., OuzzineM., Fournel-GigleuxS., LafaurieC., RadominskaA., BurchellB., SiestG., & MagdalouJ. (1993). Glucuronidation of hyodeoxycholic acid in human liver: evidence for a selective role of UDP-glucuronosyltransferase 2B4. Journal of Biological Chemistry268, 25,636–25,642.
