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dc.contributor.authorAfroz, Farhana
dc.contributor.authorJonkman, Els
dc.contributor.authorHua, Jin
dc.contributor.authorKist, Alwyn
dc.contributor.authorZhou, Yabin
dc.contributor.authorSokoya, Elke Marion
dc.contributor.authorPadbury, Robert Thomas
dc.contributor.authorNieuwenhuijs, Vincent
dc.contributor.authorBarritt, Gregory John
dc.date.accessioned2018-10-05T06:25:05Z
dc.date.available2018-10-05T06:25:05Z
dc.date.issued2018-09-01
dc.identifier.citationAfroz, F., Jonkman, E., Hua, J., Kist, A., Zhou, Y., Sokoya, E. M., … Barritt, G. (2018). Evidence that decreased expression of sinusoidal bile acid transporters accounts for the inhibition by rapamycin of bile flow recovery following liver ischemia. European Journal of Pharmacology, 838, 91–106.en_US
dc.identifier.issn1879-0712
dc.identifier.urihttp://hdl.handle.net/2328/38385
dc.descriptionThis author accepted manuscript is made available following 12 month embargo from date of publication (Sept 2018) in accordance with the publisher’s archiving policy. This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/ which permits use, distribution and reproduction in any medium, provided the original work is properly cited.en_US
dc.description.abstractRapamycin is employed as an immunosuppressant following organ transplant and, in patients with hepatocellular carcinoma, to inhibit cancer cell regrowth following liver surgery. Preconditioning the liver with rapamycin to induce the expression of antioxidant enzymes is a potential strategy to reduce ischemia reperfusion (IR) injury. However, pre-treatment with rapamycin inhibits bile flow, especially following ischemia. The aim was to investigate the mechanisms involved in this inhibition. In a rat model of segmental hepatic ischemia and reperfusion, acute administration of rapamycin by intravenous injection did not inhibit the basal rate of bile flow. Pre-treatment of rats with rapamycin for 24 h by intraperitoneal injection inhibited the expression of mRNA encoding the sinusoidal influx transporters Ntcp, Oatp1 and 2 and the canalicular efflux transporter Bsep, and increased expression of canalicular Mrp2. Dose-response curves for the actions of rapamycin on the expression of Bsep and Ntcp in cultured rat hepatocytes were biphasic, and monophasic for effects on Oatp1. In cultured tumorigenic H4IIE liver cells, several bile acid transporters were not expressed, or were expressed at very low levels compared to hepatocytes. In H4IIE cells, rapamycin increased expression of Ntcp, Oatp1 and Mrp2, but decreased expression of Oatp2. It is concluded that the inhibition of bile flow recovery following ischemia observed in rapamycin-treated livers is principally due to inhibition of the expression of sinusoidal bile acid transporters. Moreover, in tumorigenic liver tissue the contribution of tumorigenic hepatocytes to total liver bile flow is likely to be small and is unlikely to be greatly affected by rapamycin.en_US
dc.description.sponsorshipThis research was produced with the financial support of Cancer Council S.A.s Beat Cancer Project (grant number 1026478) on behalf of its donors and the State Government of South Australia through the Department of Health. The work was also supported by grants from the Flinders Foundation and Flinders University of South Australia.en_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.rights© 2018 Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.subjectRapamycinen_US
dc.subjectLiveren_US
dc.subjectIschemia reperfusionen_US
dc.subjectHepatocytesen_US
dc.subjectH4IIE liver cellsen_US
dc.subjectBile acid transportersen_US
dc.titleEvidence that decreased expression of sinusoidal bile acid transporters accounts for the inhibition by rapamycin of bile flow recovery following liver ischemiaen_US
dc.typeArticleen
dc.identifier.doihttps://doi.org/10.1016/j.ejphar.2018.08.043en_US
dc.rights.holder© 2018 Elsevier.en_US
dc.rights.licenseCC-BY-NC-ND
local.contributor.authorOrcidLookupBarritt, Gregory John: https://orcid.org/0000-0002-7472-4250en_US
local.contributor.authorOrcidLookupSokoya, Elke Marion: https://orcid.org/0000-0001-8509-2044en_US


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