Saturation of Multidrug-Resistant Protein 2 (Mrp2/Abcc2)-Mediated Hepatobiliary Secretion: Nonlinear Pharmacokinetics of a Heterocyclic Compound in Rats after Intravenous Bolus Administration

Hu, Yonghan; Sampson, Kathleen E.; Heyde, Bruce R.; Mandrell, Kathy M.; Li, Na; Zutshi, Anup; Lai, Yurong

doi:10.1124/dmd.108.024059

Cited by 10 publications

(5 citation statements)

References 19 publications

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“…The greater detoxification capacity of liver of RE vs. OF cows was substantiated by the lower plasma bilirubin (e.g., higher clearance capacity) in early lactation (Figure 1) and inferred by the higher activation of ‘Drug metabolism – other enzymes’ and ‘ABC transporters’ (File S2). The ATP binding cassette (ABC) transporters play an important role in removal of xenobiotic compounds through their excretion in bile salts [51], [52].…”

Section: Resultsmentioning

confidence: 99%

Integrative Analyses of Hepatic Differentially Expressed Genes and Blood Biomarkers during the Peripartal Period between Dairy Cows Overfed or Restricted-Fed Energy Prepartum

et al. 2014

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Using published dairy cattle liver transcriptomics dataset along with novel blood biomarkers of liver function, metabolism, and inflammation we have attempted an integrative systems biology approach applying the classical functional enrichment analysis using DAVID, a newly-developed Dynamic Impact Approach (DIA), and an upstream gene network analysis using Ingenuity Pathway Analysis (IPA). Transcriptome data was generated from experiments evaluating the impact of prepartal plane of energy intake [overfed (OF) or restricted (RE)] on liver of dairy cows during the peripartal period. Blood biomarkers uncovered that RE vs. OF led to greater prepartal liver distress accompanied by a low-grade inflammation and larger proteolysis (i.e., higher haptoglobin, bilirubin, and creatinine). Post-partum the greater bilirubinaemia and lipid accumulation in OF vs. RE indicated a large degree of liver distress. The re-analysis of microarray data revealed that expression of >4,000 genes was affected by diet × time. The bioinformatics analysis indicated that RE vs. OF cows had a liver with a greater lipid and amino acid catabolic capacity both pre- and post-partum while OF vs. RE cows had a greater activation of pathways/functions related to triglyceride synthesis. Furthermore, RE vs. OF cows had a larger (or higher capacity to cope with) ER stress likely associated with greater protein synthesis/processing, and a higher activation of inflammatory-related functions. Liver in OF vs. RE cows had a larger cell proliferation and cell-to-cell communication likely as a response to the greater lipid accumulation. Analysis of upstream regulators indicated a pivotal role of several lipid-related transcription factors (e.g., PPARs, SREBPs, and NFE2L2) in priming the liver of RE cows to better face the early postpartal metabolic and inflammatory challenges. An all-encompassing dynamic model was proposed based on the findings.

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Section: Resultsmentioning

confidence: 99%

Integrative Analyses of Hepatic Differentially Expressed Genes and Blood Biomarkers during the Peripartal Period between Dairy Cows Overfed or Restricted-Fed Energy Prepartum

et al. 2014

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“…CL uptake in suspended hepatocytes was determined using cryopreserved human hepatocytes by a fast filtration approach using either a cell harvester (Micro96 Harvester, Molecular Devices, Sunnyvale, CA) or oil-spin separation as previously described. 20,21 For the cell harvester approach, cryopreserved hepatocytes were thawed in a water bath at 37 °C and then placed on ice, after which the hepatocytes were resuspended in Krebs−Henseleit buffer. Cell viability was determined by trypan blue exclusion, and the suspension was diluted to 2 × 10 incubator for 10 min, with and without inhibitors.…”

Section: ■ Introductionmentioning

confidence: 99%

Characterization of Organic Anion Transporting Polypeptide (OATP) Expression and Its Functional Contribution to the Uptake of Substrates in Human Hepatocytes

et al. 2012

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Since the substrate specificities of OATP1B1, 1B3, and 2B1 are broad and overlapping, the contribution of each isoform to the overall hepatic uptake is of concern when assessing transporter-mediated drug–drug interactions (DDIs) or genetic polymorphism impact in the clinic. Herein, we quantitatively measured OATP proteins in cryopreserved hepatocytes, sandwich-cultured human hepatocytes (SCHH), and the liver, and examined the relationship with functional uptake of OATP substrates in an effort to identify the OATP isoform(s) contributing to the hepatic uptake of pitavastatin. The modulation of OATP expression in SCHH was found to be lot-dependent. However, OATP protein measurements averaged from 5 lots of SCHH were comparable to that of suspended hepatocytes. All three OATP transporters in suspended hepatocytes and SCHH were significantly lower than those in the liver. In SCHH, the uptake of CCK-8 and pravastatin was found to be associated with the expression of OATP1B3 and OATP1B1, respectively. In suspended hepatocytes, OATP1B1 appeared to show a positive trend with respect to the uptake of pitavastatin, which suggests a selective contribution of OATP1B1 to pitavastatin transport and thus an OATP quantitative protein expression–activity relationship. While the passive diffusion of rosuvastatin in SCHH was consistent across hepatocyte lots, the passive diffusion of pitavastatin varied over a broad range (>4-fold) in suspended hepatocytes and was inversely correlated with transporter-mediated uptake, presumably due to cell membrane alterations imparted by cryopreservation. Collectively, SCHH maintains OATP protein expression and membrane integrity and, if feasible when considering research goals, would be considered a superior tool for the characterization of in vitro transport parameters without the complication of membrane leakage.

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“…Multidrug resistance-associated protein 2 (MRP2) is predominantly found in the canalicular membrane of polarized hepatocytes and mediates biliary excretion of endogenous or exogenous substances. 27 Analysis of MRP2 localization in human clusters within the chimeric livers revealed not only positive staining but also a distribution resembling normal human liver tissues ( Fig. 4D ).…”

Section: Resultsmentioning

confidence: 90%

Primary Human Hepatocytes Repopulate Livers of Mice AfterIn VitroCulturing and Lentiviral-Mediated Gene Transfer

Bierwolf¹,

Volz

Lütgehetmann

et al. 2016

Tissue Engineering Part A

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Cell-based therapies represent a promising alternative to orthotopic liver transplantation. However, therapeutic effects are limited by low cell engraftment rates. We recently introduced a technique creating human hepatocyte spheroids for potential therapeutic application. The aim of this study was to evaluate whether these spheroids are suitable for engraftment in diseased liver tissues. Intrasplenic spheroid transplantation into immunodeficient uPA/SCID/beige mice was performed. Hepatocyte transduction ability prior to transplantation was tested by lentiviral labeling using red-green-blue (RGB) marking. Eight weeks after transplantation, animals were sacrificed and livers were analyzed by immunohistochemistry and immunofluorescence. To investigate human hepatocyte-specific gene expression profiles in mice, quantitative real-time-PCR was applied. Human albumin and alpha-1-antitrypsin concentrations in mouse serum were quantified to assess the levels of human chimerism. Precultured human hepatocytes reestablished their physiological liver tissue architecture and function upon transplantation in mice. Positive immunohistochemical labeling of the proliferating cell nuclear antigen revealed that human hepatocytes retained their in vivo proliferation capacity. Expression profiles of human genes analyzed in chimeric mouse livers resembled levels determined in native human tissue. Extensive vascularization of human cell clusters was detected by demonstration of von Willebrand factor activity. To model gene therapy approaches, lentiviral transduction was performed ex vivo and fluorescent microscopic imaging revealed maintenance of RGB marking in vivo. Altogether, this is the first report demonstrating that cultured and retroviral transduced human hepatocyte spheroids are able to engraft and maintain their regenerative potential in vivo.

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Saturation of Multidrug-Resistant Protein 2 (Mrp2/Abcc2)-Mediated Hepatobiliary Secretion: Nonlinear Pharmacokinetics of a Heterocyclic Compound in Rats after Intravenous Bolus Administration

Cited by 10 publications

References 19 publications

Integrative Analyses of Hepatic Differentially Expressed Genes and Blood Biomarkers during the Peripartal Period between Dairy Cows Overfed or Restricted-Fed Energy Prepartum

Integrative Analyses of Hepatic Differentially Expressed Genes and Blood Biomarkers during the Peripartal Period between Dairy Cows Overfed or Restricted-Fed Energy Prepartum

Characterization of Organic Anion Transporting Polypeptide (OATP) Expression and Its Functional Contribution to the Uptake of Substrates in Human Hepatocytes

Primary Human Hepatocytes Repopulate Livers of Mice AfterIn VitroCulturing and Lentiviral-Mediated Gene Transfer

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