The molecular and cellular mechanisms of 1,2-dichlorobenzene induced liver injury in Fischer-344 and Sprague-Dawley rats

Persistent Link:
http://hdl.handle.net/10150/290190
Title:
The molecular and cellular mechanisms of 1,2-dichlorobenzene induced liver injury in Fischer-344 and Sprague-Dawley rats
Author:
Younis, Husam S.
Issue Date:
2001
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
1,2-Dichlorobenzene (1,2-DCB), an industrial solvent, is a potent hepatotoxicant in Fischer-344 (F-344) rats. Bioactivation of 1,2-DCB by cytochrome P450 enzymes in the liver and subsequent activation of Kupffer cells (KC), the resident liver macrophages, are required for the development and progression of liver damage. The mechanisms by which KC cells become activated in chemical induced liver injury are unknown. The studies described in this dissertation utilized 1,2-DCB as a model hepatotoxicant to test the hypothesis that KC activation following 1,2-DCB induced liver injury is triggered by molecular and cellular events in hepatocytes that lead to the expression of proteins known to activate inflammatory cells. The administration of 1,2-DCB (3.6mmol/kg, i.p.) to F-344 rats or incubation of 1,2-DCB (3.6 umol) with primary cultured hepatocytes of F-344 rats produces an intracellular oxidative stress as assessed by the production of glutathione disulfide. The binding activity of transcription factors associated with oxidative stress (AP-1, EpRE and NF-kB) were also enhanced in F-344 rat hepatocytes by 2 to 6 hr of incubation with 1,2-DCB. After 12 hr of incubation with 1,2-DCB, the production and release of CINC was 2.2-fold greater in F-344 rat hepatocytes than control cells. The mRNA expression of the chemokine MIF was also increased by 1,2-DCB in F-344 rat hepatocytes. In contrast, these molecular and cellular events were delayed or significantly reduced in the hepatocytes of the Sprague-Dawley rat, which is much less sensitive to 1,2-DCB induced hepatotoxicity. Furthermore, KC incubated with conditioned media from F-344 rat hepatocytes treated with 1,2-DCB for 24 hr showed enhanced NF-kB binding activity. Interestingly, the receptor for CINC, CXC Receptor 2, was expressed on KC as determined by immunohistochemical analysis. These data suggest that hepatocellular oxidative stress may trigger a cascade of molecular processes in hepatocytes that promote the expression and release of oxidant sensitive chemokines. These products signal the activation of KC and the upregulation of the inflammatory response leading to the progression of 1,2-DCB induced liver damage.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Toxicology.; Health Sciences, Pharmacology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology and Toxicology
Degree Grantor:
University of Arizona
Advisor:
Sipes, I. Glenn

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleThe molecular and cellular mechanisms of 1,2-dichlorobenzene induced liver injury in Fischer-344 and Sprague-Dawley ratsen_US
dc.creatorYounis, Husam S.en_US
dc.contributor.authorYounis, Husam S.en_US
dc.date.issued2001en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstract1,2-Dichlorobenzene (1,2-DCB), an industrial solvent, is a potent hepatotoxicant in Fischer-344 (F-344) rats. Bioactivation of 1,2-DCB by cytochrome P450 enzymes in the liver and subsequent activation of Kupffer cells (KC), the resident liver macrophages, are required for the development and progression of liver damage. The mechanisms by which KC cells become activated in chemical induced liver injury are unknown. The studies described in this dissertation utilized 1,2-DCB as a model hepatotoxicant to test the hypothesis that KC activation following 1,2-DCB induced liver injury is triggered by molecular and cellular events in hepatocytes that lead to the expression of proteins known to activate inflammatory cells. The administration of 1,2-DCB (3.6mmol/kg, i.p.) to F-344 rats or incubation of 1,2-DCB (3.6 umol) with primary cultured hepatocytes of F-344 rats produces an intracellular oxidative stress as assessed by the production of glutathione disulfide. The binding activity of transcription factors associated with oxidative stress (AP-1, EpRE and NF-kB) were also enhanced in F-344 rat hepatocytes by 2 to 6 hr of incubation with 1,2-DCB. After 12 hr of incubation with 1,2-DCB, the production and release of CINC was 2.2-fold greater in F-344 rat hepatocytes than control cells. The mRNA expression of the chemokine MIF was also increased by 1,2-DCB in F-344 rat hepatocytes. In contrast, these molecular and cellular events were delayed or significantly reduced in the hepatocytes of the Sprague-Dawley rat, which is much less sensitive to 1,2-DCB induced hepatotoxicity. Furthermore, KC incubated with conditioned media from F-344 rat hepatocytes treated with 1,2-DCB for 24 hr showed enhanced NF-kB binding activity. Interestingly, the receptor for CINC, CXC Receptor 2, was expressed on KC as determined by immunohistochemical analysis. These data suggest that hepatocellular oxidative stress may trigger a cascade of molecular processes in hepatocytes that promote the expression and release of oxidant sensitive chemokines. These products signal the activation of KC and the upregulation of the inflammatory response leading to the progression of 1,2-DCB induced liver damage.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Toxicology.en_US
dc.subjectHealth Sciences, Pharmacology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorSipes, I. Glennen_US
dc.identifier.proquest3016483en_US
dc.identifier.bibrecord.b41930241en_US
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