Mechanisms of methylenedianiline toxicity to rat biliary epithelial cells

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dc.contributor.advisorMary F. Kanz, Ph.D.en_US
dc.contributor.committeeMemberRonald A Faris, Ph.D.en_US
dc.contributor.committeeMemberMary Treinen Moslenen_US
dc.contributor.committeeMemberKenneth S. Ramos, Ph.D.en_US
dc.contributor.committeeMemberGuillermo A. Altenberg, M.D., Ph.D.en_US
dc.contributor.committeeMemberGerald A Campbell, M.D., Ph.D.en_US
dc.creatorVincente Santa Cruzen_US
dc.date.accessioned2011-12-20T16:05:27Z
dc.date.available2002-11-06en_US
dc.date.available2011-12-20T16:05:27Z
dc.date.created2002-11-06en_US
dc.date.issued2001-05-06en_US
dc.description.abstractMethylenedianiline (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.mediumelectronicen_US
dc.identifier.otheretd-11062002-200410en_US
dc.identifier.urihttp://hdl.handle.net/2152.3/246
dc.language.isoengen_US
dc.rightsCopyright © 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.subjecttight junctionsen_US
dc.subjectmitochondriaen_US
dc.subjectmethylenedianilineen_US
dc.subjectglucose uptakeen_US
dc.subjectDAPMen_US
dc.subjectbiliary epithelial cellsen_US
dc.titleMechanisms of methylenedianiline toxicity to rat biliary epithelial cellsen_US
dc.type.genredissertationen_US
dc.type.materialtexten_US
thesis.degree.departmentExperimental Pathologyen_US
thesis.degree.grantorThe University of Texas Medical Branchen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhDen_US

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