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dc.contributor.advisorHalpert, Jamesen_US
dc.contributor.authorMILLER, NATALIE ELIZABETH.
dc.creatorMILLER, NATALIE ELIZABETH.en_US
dc.date.accessioned2011-10-31T17:00:50Z
dc.date.available2011-10-31T17:00:50Z
dc.date.issued1987en_US
dc.identifier.urihttp://hdl.handle.net/10150/184174
dc.description.abstractThe cytochrome P-450 dependent monooxygenase system plays a key role in the bioactivation and detoxication of xenobiotics. Isozyme-specific inhibitors of cytochrome P-450 may be useful in elucidating the role of particular isozymes in xenobiotic metabolism or in suppressing the bioactivation of xenobiotics and enhancing detoxication. The antibiotic chloramphenicol is a selective mechanism-based inactivator of rat liver cytochromes P-450, inactivating 6 of the 12 isozymes monitored, including the major phenobarbital-inducible isozyme PB-B. Analogs of chloramphenicol have been tested to determine the importance of various functional groups in regulating the effectiveness and isozyme selectivity of chloramphenicol as a mechanism-based inactivator of cytochromes P-450. This information will aid in the design of more effective and isozyme specific mechanism-based inactivators. The dihalomethyl group and the propanediol moiety were found to be important in determining the efficacy of inactivation and the ability to inactivate the enzyme by virtue of the modification of the protein as opposed to the modification of the heme moiety. The propanediol side chain also plays a role in the isozyme selectivity. Unlike chloramphenicol, N (2-p-nitrophenethyl)dichloroacetamide (pNO₂DCA), which contains an ethyl group in place of the propanediol side chain of chloramphenicol, is an effective inactivator of BNF-B, the major beta-naphthoflavone-inducible isozyme, as well as PB-B, in vitro and in vivo. Alkaline hydrolysis and enzymatic digestion of the covalently modified isozymes has shown that chloramphenicol and pNO₂DCA are both metabolized by cytochromes P-450 to oxamyl chlorides which bind to lysine and other amino acid residues of the enzyme. However, the mechanism by which pNO₂DCA inactivates BNF-B differs significantly from that by which chloramphenicol inactivates PB-B, although both involve an impairment of the transfer of electrons from NADPH-cytochrome P-450 reductase, suggesting that there are differences in the active sites of these two isozymes.
dc.language.isoenen_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.subjectCytochrome P-450.en_US
dc.subjectChloramphenicol.en_US
dc.subjectBiotransformation (Metabolism)en_US
dc.subjectXenobiotics -- Metabolic detoxification.en_US
dc.titleANALOGS OF CHLORAMPHENICOL AS MECHANISM-BASED INACTIVATORS OF RAT LIVER CYTOCHROMES P-450en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.identifier.oclc699800020en_US
thesis.degree.grantorUniversity of Arizonaen_US
thesis.degree.leveldoctoralen_US
dc.contributor.committeememberCarter, Deanen_US
dc.contributor.committeememberGandolfi, Jayen_US
dc.contributor.committeememberNelson, Daviden_US
dc.contributor.committeememberSipes, Glennen_US
dc.identifier.proquest8726832en_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.namePh.D.en_US
dc.description.noteThis item was digitized from a paper original and/or a microfilm copy. If you need higher-resolution images for any content in this item, please contact us at repository@u.library.arizona.edu.
dc.description.admin-noteOriginal file replaced with corrected file July 2023.
refterms.dateFOA2018-08-22T16:03:34Z
html.description.abstractThe cytochrome P-450 dependent monooxygenase system plays a key role in the bioactivation and detoxication of xenobiotics. Isozyme-specific inhibitors of cytochrome P-450 may be useful in elucidating the role of particular isozymes in xenobiotic metabolism or in suppressing the bioactivation of xenobiotics and enhancing detoxication. The antibiotic chloramphenicol is a selective mechanism-based inactivator of rat liver cytochromes P-450, inactivating 6 of the 12 isozymes monitored, including the major phenobarbital-inducible isozyme PB-B. Analogs of chloramphenicol have been tested to determine the importance of various functional groups in regulating the effectiveness and isozyme selectivity of chloramphenicol as a mechanism-based inactivator of cytochromes P-450. This information will aid in the design of more effective and isozyme specific mechanism-based inactivators. The dihalomethyl group and the propanediol moiety were found to be important in determining the efficacy of inactivation and the ability to inactivate the enzyme by virtue of the modification of the protein as opposed to the modification of the heme moiety. The propanediol side chain also plays a role in the isozyme selectivity. Unlike chloramphenicol, N (2-p-nitrophenethyl)dichloroacetamide (pNO₂DCA), which contains an ethyl group in place of the propanediol side chain of chloramphenicol, is an effective inactivator of BNF-B, the major beta-naphthoflavone-inducible isozyme, as well as PB-B, in vitro and in vivo. Alkaline hydrolysis and enzymatic digestion of the covalently modified isozymes has shown that chloramphenicol and pNO₂DCA are both metabolized by cytochromes P-450 to oxamyl chlorides which bind to lysine and other amino acid residues of the enzyme. However, the mechanism by which pNO₂DCA inactivates BNF-B differs significantly from that by which chloramphenicol inactivates PB-B, although both involve an impairment of the transfer of electrons from NADPH-cytochrome P-450 reductase, suggesting that there are differences in the active sites of these two isozymes.


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