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dc.contributor.advisorJaeschke, Hartmut
dc.contributor.authorDu, Kuo
dc.date.accessioned2018-10-22T22:04:54Z
dc.date.available2018-10-22T22:04:54Z
dc.date.issued2017-05-31
dc.date.submitted2017
dc.identifier.otherhttp://dissertations.umi.com/ku:15125
dc.identifier.urihttp://hdl.handle.net/1808/26928
dc.description.abstractAcetaminophen (APAP) overdose causes severe hepatotoxicity in animals and humans. Although numerous studies have established the existence of an extensive oxidative stress during APAP hepatotoxicity, its source, pathophysiological roles and therapeutic potentials have not been well clarified. In addition, little is known about the mechanisms of recovery of mitochondrial mass and function or the role of mitochondrial biogenesis (MB) in the injury and repair process. The primary purpose of this dissertation was to further investigate the role of mitochondria, especially mitochondrial oxidative stress and MB, in APAP hepatotoxicity. In the first study, we explored the mechanisms underlying the gender differences in susceptibility to APAP overdose in mice. We demonstrated that female mice are less susceptible to APAP hepatotoxicity. The lower susceptibility of female mice was achieved by the improved detoxification of reactive oxygen due to accelerated recovery of mitochondrial GSH levels, which attenuates late JNK activation and oxidant stress. However, even the reduced injury in female mice was still dependent on c-Jun N-terminal kinase (JNK). In the second study, we tested the therapeutic potential of targeting mitochondrial oxidant stress. We showed that mitochondria-targeted antioxidant Mito-Tempo (MT) protected against APAP hepatotoxicity in mice. It did not inhibit metabolic activation of APAP but dose-dependently attenuated mitochondrial oxidant stress and prevented the following mitochondrial dysfunction. Comparison of the protection by MT to its analog Tempo highlights the importance of mitochondrial oxidant stress in the development of APAP toxicity. Our study also demonstrated that MT as a treatment alone or together with NAC offers a better protection than NAC alone, which supports MT as a therapeutic option for APAP overdosed patients. In the third study, we demonstrated that metformin, a first-line drug to treat type 2 diabetes mellitus, protected against APAP hepatotoxicity in mice. It did not inhibit JNK activation or mitochondrial JNK translocation but significantly attenuated APAP-induced mitochondrial oxidant stress and the subsequent mitochondrial dysfunction, most likely through inhibition of mitochondrial complex I activity. In addition, metformin dose-dependently protected human HepaRG cells, a clinically relevant model for APAP overdose, against APAP induced cell injury, supporting metformin as a therapeutic option for treatment of APAP overdose or acute liver failure in patients. In the last study, we investigated the role of MB after APAP overdose. We demonstrated that MB occurs selectively in hepatocytes surrounding necrotic areas after APAP hepatotoxicity. While induction of MB protected against the injury and promoted liver regeneration, its inhibition delayed the injury and compromised the regeneration process. Induction of MB may be another promising therapeutic approach for clinical APAP overdose in the future. In summary, this dissertation further demonstrates that mitochondrial oxidant stress and dysfunction play a critical role in APAP hepatotoxicity, and targeting mitochondrial oxidant stress and MB can be promising therapeutic approaches for patients with APAP overdose.
dc.format.extent193 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectToxicology
dc.subjectPharmacology
dc.subjectMolecular biology
dc.subjectAcetaminophen
dc.subjectliver toxicity
dc.subjectmetformin
dc.subjectmitochondria
dc.subjectmito-tempo
dc.subjectoxidative stress
dc.titleMITOCHONDRIAL OXIDATIVE STRESS AND BIOGENESIS DURING ACETAMINOPHEN HEPATOTOXICITY
dc.typeDissertation
dc.contributor.cmtememberDing, Wen-Xing
dc.contributor.cmtememberApte, Udayan
dc.contributor.cmtememberPritchard, Michele
dc.contributor.cmtememberWeinman, Steven
dc.thesis.degreeDisciplinePharmacology, Toxicology & Therapeutics
dc.thesis.degreeLevelPh.D.
dc.identifier.orcid
dc.rights.accessrightsopenAccess


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