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dc.contributor.authorLarge, Emma
dc.contributor.authorHughes, David J.
dc.contributor.authorSarkar, Ujjal
dc.contributor.authorRavindra, Kodihalli C.
dc.contributor.authorYoung, Carissa L.
dc.contributor.authorRivera-Burgos, Dinelia
dc.contributor.authorYu, Jiajie
dc.contributor.authorCirit, Murat
dc.contributor.authorWishnok, John S
dc.contributor.authorLauffenburger, Douglas A
dc.contributor.authorGriffith, Linda G
dc.contributor.authorTannenbaum, Steven R
dc.date.accessioned2017-08-18T15:46:07Z
dc.date.available2017-08-18T15:46:07Z
dc.date.issued2017-06
dc.date.submitted2016-11
dc.identifier.issn0090-9556
dc.identifier.issn1521-009X
dc.identifier.urihttp://hdl.handle.net/1721.1/110981
dc.description.abstractIn vitro hepatocyte culture systems have inherent limitations in capturing known human drug toxicities that arise from complex immune responses. Therefore, we established and characterized a liver immunocompetent coculture model and evaluated diclofenac (DCF) metabolic profiles, in vitro–in vivo clearance correlations, toxicological responses, and acute phase responses using liquid chromatography–tandem mass spectrometry. DCF biotransformation was assessed after 48 hours of culture, and the major phase I and II metabolites were similar to the in vivo DCF metabolism profile in humans. Further characterization of secreted bile acids in the medium revealed that a glycine-conjugated bile acid was a sensitive marker of dose-dependent toxicity in this three-dimensional liver microphysiological system. Protein markers were significantly elevated in the culture medium at high micromolar doses of DCF, which were also observed previously for acute drug-induced toxicity in humans. In this immunocompetent model, lipopolysaccharide treatment evoked an inflammatory response that resulted in a marked increase in the overall number of acute phase proteins. Kupffer cell–mediated cytokine release recapitulated an in vivo proinflammatory response exemplified by a cohort of 11 cytokines that were differentially regulated after lipopolysaccharide induction, including interleukin (IL)-1β, IL-1Ra, IL-6, IL-8, IP-10, tumor necrosis factor-α, RANTES (regulated on activation normal T cell expressed and secreted), granulocyte colony-stimulating factor, macrophage colony-stimulating factor, macrophage inflammatory protein-1β, and IL-5. In summary, our findings indicate that three-dimensional liver microphysiological systems may serve as preclinical investigational platforms from the perspective of the discovery of a set of clinically relevant biomarkers including potential reactive metabolites, endogenous bile acids, excreted proteins, and cytokines to predict early drug-induced liver toxicity in humans.en_US
dc.language.isoen_US
dc.publisherAmerican Society for Pharmacology & Experimental Therapeutics (ASPET)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1124/dmd.116.074005en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alikeen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/en_US
dc.sourceProf. Griffith via Howard Silveren_US
dc.titleIntegrated Assessment of Diclofenac Biotransformation, Pharmacokinetics, and Omics-Based Toxicity in a Three-Dimensional Human Liver-Immunocompetent Coculture Systemen_US
dc.typeArticleen_US
dc.identifier.citationSarkar, Ujjal et al. “Integrated Assessment of Diclofenac Biotransformation, Pharmacokinetics, and Omics-Based Toxicity in a Three-Dimensional Human Liver-Immunocompetent Coculture System.” Drug Metabolism and Disposition 45, 7 (April 2017): 855–866 © 2017 The Author(s)en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemistryen_US
dc.contributor.approverGriffith, Lindaen_US
dc.contributor.mitauthorSarkar, Ujjal
dc.contributor.mitauthorRavindra, Kodihalli C.
dc.contributor.mitauthorYoung, Carissa L.
dc.contributor.mitauthorRivera-Burgos, Dinelia
dc.contributor.mitauthorYu, Jiajie
dc.contributor.mitauthorCirit, Murat
dc.contributor.mitauthorWishnok, John S
dc.contributor.mitauthorLauffenburger, Douglas A
dc.contributor.mitauthorGriffith, Linda G
dc.contributor.mitauthorTannenbaum, Steven R
dc.relation.journalDrug Metabolism and Dispositionen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsSarkar, Ujjal; Ravindra, Kodihalli C.; Large, Emma; Young, Carissa L.; Rivera-Burgos, Dinelia; Yu, Jiajie; Cirit, Murat; Hughes, David J.; Wishnok, John S.; Lauffenburger, Douglas A.; Griffith, Linda G.; Tannenbaum, Steven R.en_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-8581-1261
dc.identifier.orcidhttps://orcid.org/0000-0002-9618-8495
dc.identifier.orcidhttps://orcid.org/0000-0001-6975-5047
dc.identifier.orcidhttps://orcid.org/0000-0002-2325-552X
dc.identifier.orcidhttps://orcid.org/0000-0002-1801-5548
mit.licenseOPEN_ACCESS_POLICYen_US
mit.metadata.statusComplete


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