title: Comparative study of CYP2B1/2 induction and the transport of bilirubin and taurocholate in rat hepatocyte-mono- and hepatocyte-Kupffer cell co-cultures.
abstract: BACKGROUND
  Hepatocyte-Kupffer cell (KC) co-cultures represent a promising approach for in vitro modeling of complex interactions between parenchymal and non-parenchymal cells in the liver, responsible for drug-induced liver injury (DILI). In this study we aimed to compare hepatocyte monocultures with hepatocyte-KC co-cultures regarding some basic liver functions associated with the chemical defense system. These pathways involve transporters and enzymes the function of which is highly sensitive towards hepatotoxic events.
  
  
  METHODS
  CYP2B1/2 induction and the biliary and sinusoidal elimination of bilirubin (B) and taurocholate (TC) were studied in rat hepatocyte sandwich cultures compared with rat hepatocyte-KC sandwich co-cultures of 1:0, 6:1, 2:1 and 1:1 cell combinations representing the physiologic and pathologic conditions of the liver.
  
  
  RESULTS
  KCs decreased phenobarbital inducibility of CYP2B1/2 in a cell ratio dependent manner and activation of KCs by lipopolisacharide (LPS) amplified this effect. Similarly, KCs decreased the transport of B and its glucuronides (BG) in both sinusoidal and canalicular directions resulting in its intracellular accumulation. In contrast, the uptake and the efflux of TC were greater in the co-cultures than in the hepatocyte monocultures. Immuno-labelling of sodium-dependent taurocholate transporter (Ntcp) revealed increased expression of the transporter in the presence of KCs.
  
  
  CONCLUSIONS
  Here we presented that KCs have a direct impact on some hepatocyte functions suggesting that the co-culture model may be more suitable for drug related hepatotoxicity studies than hepatocyte monocultures.
authors.affiliation: Department of Functional Pharmacology, Institute of Organic Chemistry, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar tudósok körútja 2, Hungary. Electronic address: flax84@gmail.com.
authors.forename: Attila
authors.initials: A
authors.lastname: Bátai-Konczos
authors.affiliation: Department of Functional Pharmacology, Institute of Organic Chemistry, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar tudósok körútja 2, Hungary. Electronic address: veres.zsuzsanna@ttk.mta.hu.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Veres
authors.affiliation: Department of Functional Pharmacology, Institute of Organic Chemistry, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar tudósok körútja 2, Hungary. Electronic address: szabo.monika@ttk.mta.hu.
authors.forename: Mónika
authors.initials: M
authors.lastname: Szabó
authors.affiliation: Department of Functional Pharmacology, Institute of Organic Chemistry, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar tudósok körútja 2, Hungary. Electronic address: ioja.eniko@ttk.mta.hu.
authors.forename: Enikő
authors.initials: E
authors.lastname: Ioja
authors.affiliation: Department of Immunology, Institute of Biology, Eötvös Loránd University, 1117 Budapest, Pázmány Péter sétány 1/c, Hungary. Electronic address: glorial@caesar.elte.hu.
authors.forename: Glória
authors.initials: G
authors.lastname: László
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar tudósok körútja 2, Hungary. Electronic address: torok.gyorgy@ttk.mta.hu.
authors.forename: György
authors.initials: G
authors.lastname: Török
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar tudósok körútja 2, Hungary. Electronic address: homolya.laszlo@ttk.mta.hu.
authors.forename: László
authors.initials: L
authors.lastname: Homolya
authors.affiliation: Department of Functional Pharmacology, Institute of Organic Chemistry, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar tudósok körútja 2, Hungary. Electronic address: jemnitz.katalin@ttk.mta.hu.
authors.forename: Katalin
authors.initials: K
authors.lastname: Jemnitz
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D001663:Bilirubin / Q000378:metabolism*; D001692:Biological Transport; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism; D018920:Coculture Techniques; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis*; D004347:Drug Interactions; D004790:Enzyme Induction; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D007728:Kupffer Cells / Q000187:drug effects / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D050216:Metabolic Detoxication, Phase I; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D013656:Taurocholic Acid / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C482199:lipopolysaccharide, E coli O55-B5; D013656:Taurocholic Acid; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; C025619:steroid 16-beta-hydroxylase; D001663:Bilirubin
keywords: CYP2B1/2; Hepatocyte; Kupffer cell; Sandwich co-culture method; Transporters