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ANALOGS OF CHLORAMPHENICOL AS MECHANISM-BASED INACTIVATORS OF RAT LIVER CYTOCHROMES P-450.MILLER, NATALIE ELIZABETH. January 1987 (has links)
The 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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Selective inactivation of four rat liver microsomal androstenedione hydroxylases by chloramphenicol analogsStevens, Jeffrey Charles, 1963- January 1988 (has links)
The steroid androstenedione has been shown to be a valuable tool for the study of selective inactivation of rat liver cytochrome P-450 isozymes. The validity of this method was investigated using microsomes, purified cytochromes P-450, cytochrome P-450 antibodies, and the mechanism-based inactivator chloramphenicol. Enzyme inactivation and antibody inhibition studies show that microsomes from phenobarbital- and non-phenobarbital-treated rats are needed to accurately monitor the inactivation of the major phenobarbital-inducible P-450 isozyme (PB-B) and of the major constitutive androstenedione 16-alpha hydroxylase (UT-A). Enzyme inactivation studies showed that the antibiotic chloramphenicol caused different rates of NADPH-dependent enzyme inactivation among four androstenedione hydroxylases (16-beta > 6-beta > 16-alpha > 7-alpha). The results with twelve chloramphenicol analogs show that their selectivity as cytochrome P-450 inactivators is dependent upon at least three structural features: (1) the number of halogen atoms, (2) the presence of a para-nitro group on the phenyl ring, and (3) substitutions on the ethyl side chain.
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Induction of estradiol-2-hydroxylase by isoprenyl compounds.January 1998 (has links)
by Wong Che-cheuk, Dobe. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 98-112). / Abstract also in Chinese. / Acknowledgements --- p.i / Abstracts --- p.ii / List of Abbreviation --- p.vi / Table of Contents --- p.vii / Chapter 1. --- Introduction / Chapter 1.1 --- Stages of Cancer Development --- p.1 / Chapter 1.2 --- Comparison of Breast Cancer in Hong Kong & the United States --- p.2 / Chapter 1.2.1 --- Statistics of Breast Cancer in the United States --- p.2 / Chapter 1.2.2 --- Statistics of Breast Cancer in Hong Kong --- p.2 / Chapter 1.3 --- Factors for Breast Cancer --- p.6 / Chapter 1.3.1 --- Genetic Factor --- p.6 / Chapter 1.3.2 --- Hormonal Factor --- p.7 / Chapter 1.3.3 --- Genetic Bias --- p.9 / Chapter 1.3.4 --- Influence of Diet --- p.10 / Chapter 1.3.5 --- Obesity --- p.14 / Chapter 1.3.6 --- Xenoestrogen --- p.14 / Chapter 1.4 --- Hormonal Therapy in Breast Cancer --- p.15 / Chapter 1.4.1 --- Antiestrogen --- p.15 / Chapter 1.4.2 --- Progestin Antagonist --- p.19 / Chapter 1.4.3 --- Aromatase Inhibitor --- p.20 / Chapter 1.4.4 --- Gonadotropin Releasing Hormone (GnRH) Analogue --- p.23 / Chapter 1.5 --- Metabolism of Estrogen --- p.25 / Chapter 1.6 --- Substance with Chemopreventive Properties towards Breast Cancer --- p.29 / Chapter 1.7 --- Aryl Hydrocarbon Receptor --- p.33 / Chapter 1.8 --- Cytochrome P450s --- p.34 / Chapter 1.9 --- Yuehchukene --- p.36 / Chapter 1.10 --- Objectives of the Present Study --- p.38 / Chapter 2. --- Materials and Methods / Chapter 2.1 --- Animals --- p.40 / Chapter 2.2 --- Animal Treatment --- p.40 / Chapter 2.3 --- Preparation of Crude Microsomal Fraction --- p.41 / Chapter 2.4 --- Protein Assay --- p.41 / Chapter 2.5 --- Ethoxyresorufm-O-deethylase Assay --- p.41 / Chapter 2.6 --- Methoxyresorufin-O-deethylase Assay --- p.42 / Chapter 2.7 --- Estradiol-2-hydroxylase Assay --- p.42 / Chapter 2.8 --- Progesterone Hydroxylase Assay --- p.43 / Chapter 2.9 --- Hepatic Aromatase Activity Assay --- p.43 / Chapter 2.10 --- Inhibition of Ethoxyresorufm-O-deethylase and Estradiol-2-hydroxylase --- p.44 / Chapter 2.11 --- Free Radicals Scavenging Assay --- p.44 / Chapter 2.12 --- Chemicals --- p.45 / Chapter 3. --- Result / Chapter 3.1 --- Optimization of Condition --- p.47 / Chapter 3.1.1 --- Dosage --- p.47 / Chapter 3.1.2 --- Time for Sacrifice --- p.47 / Chapter 3.2 --- "Effect of Isoprenyl Compounds on the Body Weight, Liver Weight and Hepatic Microsomal Protein Content" --- p.50 / Chapter 3.3 --- Hepatic Enzyme Activities --- p.54 / Chapter 3.3.1 --- Ethoxyresorufm-O-deethylase --- p.54 / Chapter 3.3.2 --- Methoxyresorufm-O-deethylase --- p.57 / Chapter 3.3.3 --- Estradiol-2-hydroxylase --- p.60 / Chapter 3.3.4 --- Progesterone Hydroxylase --- p.62 / Chapter 3.3.5 --- Aromatase --- p.65 / Chapter 3.4 --- Effect of Inhibitors in Ethoxyresorufin-O-deethylase and Estradiol-2-hydroxylase Activity --- p.65 / Chapter 3.5 --- Free Radical Scavenging Activity --- p.72 / Chapter 4. --- Discussion --- p.77 / Chapter 5. --- Conclusion --- p.95 / Chapter 6. --- References --- p.98 / Chapter 7. --- Appendix --- p.113
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Cytochrome P450 activity and pollutant exposure in New Zealand native birdsNumata, Mihoko, n/a January 2006 (has links)
Birds are potentially vulnerable to the toxicity of certain environmental pollutants due to limited detoxification capabilities of their liver microsomal cytochrome P450 (CYP) enzymes. In wild birds, ethoxyresorufin O-deethylation (EROD) activity, a marker of CYP1A activity in mammals and domestic chickens, has been used as a biomarker of exposure to polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). The aim of the present study was to investigate hepatic CYP activity as an indication of detoxification capacity in New Zealand birds. In addition to the use of conventional in vitro CYP activity assays, the applicability of a noninvasive CYP activity assay was tested using caffeine as the in vivo substrate.
The ontogeny of liver microsomal 3-hydroxylation of quinine, a marker of human CYP3A activity, was investigated in Adelie penguins (Pygoscelis adeliae) from Ross Island, Antarctica. The results indicate that chicks (2-4 weeks old) possess a CYP3A-like isoform(s) as active as but not identical to the CYP3A-like isoform(s) in adults. Total CYP content was low at 2 weeks of age and increased rapidly and linearly approaching adult levels by 4 weeks of age implying a rapid development of CYPs other than the CYP3A-like isoform(s).
The main study was conducted on adult (and some post-fledging immature) birds of two native species, the herbivorous paradise shelduck (Tadorna variegata) and the omnivorous southern black-backed gull (Larus dominicanus). Birds were shot for liver collection at three sites in the South Island of New Zealand; West Coast, Lake Waipori and Dunedin landfill, in 2001-2002. The results indicate that shelducks posssess multiple CYP isoforms that independently catalyse EROD, p-nitrophenol hydroxylation (p-NP) and erythromycin demethylation (EMD), markers of mammalian CYP1A, CYP2E and CYP3A activity, respectively. In contrast, gulls appear to possess a single isoform catalysing both EROD and p-NP but possess no isoform capable of catalysing EMD.
EROD activity was high in shelducks and gulls from the landfill site, although it was not significantly associated with liver concentrations of PCBs (0.079-6.2 and 8.2-310 ng/g in shelducks and gulls, respectively), PCDD/PCDFs, toxic equivalents (TEQs) and dichlorodiphenyldichloroethylene (DDE) (0.85-317 and 44-4800 ng/g in shelducks and gulls, respectively) in either species. In shelduck livers from the landfill site, EROD was positively associated with Pb concentration but negatively associated with Hg concentration. Assessment of PCB congener patterns based on concentration ratios of individual congeners to the reference congener, 2,2�,4,4�,5,5�-hexachlorobiphenyl (IUPAC #153), indicate that the metabolism of 2,4,4�-trichlorobiphenyl (PCB#28) and 2,4,4�,5-tetrachlorobiphenyl (PCB#74) is inducible in shelducks but not in gulls. Hepatic reduced glutathione (GSH) content was higher in gulls than in shelducks suggesting greater resistance to oxidative stress in gulls.
The in vivo caffeine metabolism test as a noninvasive method to determine CYP1A activity in shelducks and gulls gave a positive outcome. The test was performed by administration of a single intraperitoneal dose of caffeine (1 mg/kg body weight) followed by blood collection at 2 and 4 h after caffeine administration for determination of the serum concentration ratio of the metabolite, paraxanthine, to caffeine (PX/CA) by HPLC. In both species, the PX/CA ratio was markedly increased by pretreatment with the model CYP1A inducer, β-naphthoflavone (BNF). BNF treatment also increased EROD activity determined after death (80-fold and 20-fold compared to controls in shelducks and gulls, respectively). However, sensitivity of the PX/CA ratio approach was lower in gulls than in shelducks due presumably to the formation of unidentified caffeine metabolites in gulls. Immunoblot analysis failed to reveal increased CYP protein levels caused by BNF treatment in shelducks and gulls due to poor cross-reactivity of avian proteins with polyclonal antibodies raised against mammalian CYPs.
EROD activity was also determined in livers of the piscivorous yellow-eyed penguin (Megadyptes antipodes) (1 chick, 3 post-fledging immature, 1 adult) from Otago, South Island of New Zealand, and found to be below the limit of quantitation. The adult liver contained 18.5 ng/g of total PCBs suggesting that EROD in this species is insensitive to induction. Comparison of the PCB congener pattern based on [PCBx]/[PCB#153] between the penguin and its putative source of PCB exposure, New Zealand marine fish, indicates that CYPs in yellow-eyed penguins metabolise 2,2�,5,5�-tetrachlorobiphenyl (PCB#52) and 2,2�,4,5,5�-pentachlorobiphenyl (PCB#101) as in many other avian species.
The findings of this study highlight substantial species differences in CYP activity in wild birds. Whether CYP expression in New Zealand birds is genetically distinct from birds in other parts of the world may warrant further investigation.
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Modulation of gene expression and DNA adduct formation by chlorophyllin in human mammary cells exposed to benzopyrenesJohn, Kaarthik. January 2006 (has links)
Thesis (Ph. D.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains xiv, 139 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 129-138).
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Predictions of kinetic parameters for the CYP2C9 substrates phenytoin and tolbutamide and the inhibitor fluconazole /Qiu, Wei, January 2000 (has links)
Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 128-147).
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Contribution à l'étude des P450 impliqués dans la biosynthèse des furocoumarinesLarbat, Romain Bourgaud, Frédéric January 2006 (has links) (PDF)
Thèse de doctorat : Sciences Agronomiques : INPL : 2006. / Titre provenant de l'écran-titre. Bibliogr.
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Les enzymes de biotransformation des xénobiotiques chez Helix aspersa (escargot) et Pleurozium schreberi (mousse) biomarqueurs potentiels de la pollution atmosphérique par des hydrocarbures aromatiques polycycliques /Ismert, Muriel. Bagrel, Denyse. January 2000 (has links) (PDF)
Thèse doctorat : Ecotoxicologie : Metz : 2000. / Thèse soutenue sur ensemble de travaux. Bibliogr. Index.
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Analyse fonctionnelle de deux cytochromes P450 de la famille CYP98 chez Nicotiana tabacumMillion-Rousseau, Rachel Reichhart, Danièle. January 2007 (has links) (PDF)
Thèse doctorat : Biologie Moléculaire et Cellulaire : Strasbourg 1 : 2006. / Titre provenant de l'écran-titre. Bibliogr. 15 p.
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Comparison of in vitro and in vivo inhibition potencies of fluvoxamine toward CYPIA2 and CYP2C19 /Yao, Caiping. January 2001 (has links)
Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 126-139).
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