Mechanisms of methylenedianiline toxicity to rat biliary epithelial cells

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Mechanisms of methylenedianiline toxicity to rat biliary epithelial cells

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dc.contributor.advisor Mary F. Kanz, Ph.D. en_US
dc.creator Vincente Santa Cruz en_US
dc.date.accessioned 2011-12-20T16:05:27Z
dc.date.available 2002-11-06 en_US
dc.date.available 2011-12-20T16:05:27Z
dc.date.created 2002-11-06 en_US
dc.date.issued 2001-05-06 en_US
dc.identifier.other etd-11062002-200410 en_US
dc.identifier.uri http://hdl.handle.net/2152.3/246
dc.description.abstract Methylenedianiline (4,4’-diaminodiphenylmethane, DAPM), a compound used to produce polyurethanes and epoxy resins, rapidly injures biliary epithelial cells (BEC) of rats in vivo. DAPM also increases biliary inorganic phosphate and glucose, suggesting that DAPM loosens hepatic tight junctions. Early ultrastructural alterations in BEC mitochondria, however, suggested a possible role of mitochondrial dysfunction in the ability of BEC to maintain glucose transport and tight junction integrity. The working hypothesis for this dissertation project was that DAPM alters tight junction integrity and/or glucose absorption by mechanisms involving mitochondrial injury. The proposed aims were to: 1). Assess tight junction integrity in vivo using a “sleeping” rat model and radioactive, non-electrolyte tracers. 2). Develop an in vitro model of DAPM injury using primary cultures of polarized rat BEC. 3). Determine if BEC tight junction integrity is altered by DAPM/ metabolite(s) in vitro using both electrophysiological and conventional tracer methods. 4). Determine if DAPM/ metabolite(s) induce mitochondrial dysfunction in BEC by assessing cellular ATP levels and mitochondrial membrane potentials. 5). Determine if BEC glucose uptake is altered following exposure to analog, alpha-methyl-D-glucopyranoside. Numerous in vivo and in vitro methods were combined to develop a model of polarized rat BEC monolayers that were assessed for changes in TJ integrity, glucose uptake and mitochondrial function after exposure to bile from untreated rats, rats treated with vehicle, or rats treated with DAPM. This model confirmed prior studies that demonstrated increased hepatobiliary tight junction permeability following DAPM treatment in vivo. Tight junctions between BEC in vitro showed both increased “leakiness” and decreased ion selectivity following exposure to bile from DAPM-treaded rats (DAPM-Bile). Furthermore, this model indicated that BEC ATP levels and mitochondrial membrane potentials were altered prior to any changes in tight junction integrity and glucose absorption. These data support the working hypothesis that mitochondria are the initial site of DAPM injury in BEC and that mitochondrial dysfunction may indirectly impair BEC glucose uptake and tight junction integrity. en_US
dc.format.medium electronic en_US
dc.language.iso eng en_US
dc.rights Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works. en_US
dc.subject tight junctions en_US
dc.subject mitochondria en_US
dc.subject methylenedianiline en_US
dc.subject glucose uptake en_US
dc.subject DAPM en_US
dc.subject biliary epithelial cells en_US
dc.title Mechanisms of methylenedianiline toxicity to rat biliary epithelial cells en_US
dc.type.material text en_US
dc.type.genre dissertation en_US
thesis.degree.name PhD en_US
thesis.degree.level Doctoral en_US
thesis.degree.grantor The University of Texas Medical Branch en_US
thesis.degree.department Pathology en_US
dc.contributor.committeeMember Ronald A Faris, Ph.D. en_US
dc.contributor.committeeMember Mary Treinen Moslen en_US
dc.contributor.committeeMember Kenneth S. Ramos, Ph.D. en_US
dc.contributor.committeeMember Guillermo A. Altenberg, M.D., Ph.D. en_US
dc.contributor.committeeMember Gerald A Campbell, M.D., Ph.D. en_US

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