29 research outputs found
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Antioxidant reactions of vitamin E in rat liver
No full textAntioxidant reactions of vitamin E (α-tocopherol, α-TH) were studied by examining the fate of α-TH during oxidative challenge to isolated rat liver mitochondria and isolated perfused rat liver. The overall goal of this dissertation was to identify the products of antioxidant reactions of α-TH and to determine the relationship between the status of α-TH, lipid peroxidation, and mitochondrial function. In isolated mitochondria, products of α-TH oxidation induced by the radical initiator 2,2'-azobis(2-amidinopropane) dihydrochloride (ABAP) were α-tocopherolquinone (α-TQ), α-tocopherolquinone-2,3-oxide (α-TQE1), and α-tocopherolquinone-5,6-oxide (α-TQE2). ABAP induced lipid peroxidation after 50% of the initial α-TH was depleted and decreased the respiratory control ratio and state 3 and state 4 respiration. In isolated perfused rat liver, the principal products of α-TH oxidation induced by tert-butylhydroperoxide (t-BuOOH) were α-TQ and epoxyquinones α-TQE1/α-TQE2, which were formed from acid-labile 8a-substituted tocopherones and epoxyhydroperoxytocopherones, respectively. t-BuOOH increased gluconeogenesis and decreased ketogenesis, as indicated by increases in lactate and pyruvate and decreases in acetoacetate (AA) and β-hydroxybutyrate β-HBA) in the effluent. In addition, there was a shift to a more oxidized state in mitochondria, as evidenced by a decrease in the β-HBP/AA ratio, a measure of NADH/NAD⁺ ratio in the mitochondria. t-BuOOH increased lipid peroxidation, which was measured by thiobarbituric acid-reactive substances in the effluent and decreased the mitochondrial respiratory control ratio. Dietary supplementation with α-TH increased α-TH levels 7-10 fold, decreased hepatic lipid peroxidation and reversed the mitochondrial uncoupling effects of t-BuOOH, but did not effect changes in metabolism. These studies provide the first comprehensive description of the oxidative turnover of vitamin E in a biological system.This 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 [email protected] file replaced with corrected file October 2023
2013 Distinguished Alumni Awards & Athletic Hall of Fame Inductees
No full text19 p.Recipient of the Distinguished Achievement Award was Daniel Nepstad '79. Recipient of the Distinguished Service Award was Richard L. Halpert '69. Recipient of the Young Alumni Award was Jeffrey M. Marinucci '00. Recipient of the Weimer K. hicks Award was Joellen L. Silberman. Special Recognition for David L. Easterbrook '69, the 2012 Distinguished Service Award Recipient. Inductees of the Athletic Hall of Fame were Jack M. Hosner '88, Ven R. Johnson '83, Julie E. Redner '81, Dirk S. H. Rhinehart '03, the 1991 Men's Tennis Team, the 1992 Men's Tennis Team, and the 1993 Men's Tennis Team
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The role of metabolic activation and oxidant injury in the hepatotoxicity of 1,2-dichlorobenzene in the rat
No full text1,2-Dichlorobenzene (1,2-DCB) is a potent hepatotoxicant in the Fischer-344 (F344) rat. Phenobarbital (PB), a known inducer of cytochrome P-450, enhanced the metabolism and covalent binding of 1,2-DCB in F344 rat liver microsomes. Identification of 2,3-dichlorophenol, 3,4-dichlorophenol and dichlorobenzene dihydrodiol indicated the formation of dichlorobenzene epoxides in PB induced microsomes. Moreover, modulation of microsomal metabolism and covalent binding using glutathione, trichloropropene oxide, ascorbic acid and superoxide dismutase implicated quinones as the major covalent binding species of 1,2-DCB. These findings indicate that 1,2-DCB is activated by cytochrome P-450 to reactive intermediates that may initiate hepatocellular injury. The hepatotoxicity of 1,2-DCB was also studied in normal F344 rats administered methyl palmitate (MP) to inhibit Kupffer cell function or superoxide dismutase (conjugated to polyethylene glycol, i.e. PEG-SOD) to scavenge superoxide anions. Both agents markedly reduced the severity of 1,2-DCB induced liver injury in normal rats. However, MP and PEG-SOD did not inhibit the PB potentiated hepatotoxicity of 1,2-DCB. In summary, the data presented in this dissertation strongly support a role for Kupffer cell derived superoxide anions in the hepatotoxicity of 1,2-DCB in normal F344 rats. Since Sprague-Dawley (SD) rats are less susceptible to the hepatotoxicity of 1,2-DCB than F344 rats, markers of oxidant injury were assessed in both strains of rats following administration of 1,2-DCB. 1,2-DCB treatment did not deplete hepatic vitamin E in F344 or SD rats. However, 1,2-DCB treated F344 rats exhibited greater ethane exhalation than SD rats, at a time when differences in GSH depletion between the two strains were most prominent and prior to the initial appearance of toxicity in F344 rats. The results further confirmed the involvement of oxidative injury in the hepatotoxicity of 1,2-DCB. It is concluded that two key events are involved in the hepatotoxicity of 1,2-DCB (1) metabolism of 1,2-DCB by cytochrome P-450 to reactive intermediates that initiate cell injury (2) oxidative injury induced by Kupffer cell derived active oxygen species, that contributes to the progression of the injury.This item was digitized from a paper original and/or a microfilm copy. If you need
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Functional characterization of hepatic microsomal and heterologousely expressed rabbit cytochrome P450 2B enzymes
No full textThe objective of the research described in this dissertation was to characterize the function of four closely related cytochrome P450 2B enzymes in the rabbit. Although these enzymes display greater than 97% amino acid sequence identity, their expression is highly variable between different organs and in different individuals. Transient and stable heterologous expression systems were used to study the distinct catalytic properties of each P450 2B enzyme. Cytochrome P450 2B5 was found to have a unique pattern of catalytic activities in comparison to the P450 2B4, 2B-B1, and 2B-Bx forms. The regio- and stereoselectivity of hydroxylation of androstenedione in hepatic microsomes depended upon whether the animal expressed cytochrome P450 2B5. Whereas the catalytic activities of P450 2B5 were characterized by high steroid hydroxylase activities, P450 2B4 had relatively low steroid hydroxylase activity and much higher activity towards the non-steroid substrates than 2B5. Androstenedione 15α-hydroxylation and benzyloxyresorufin O-debenzylation were identified as selective markers of the activity of P450 2B5 and 2B4, respectively. Phencyclidine selectively inactivated P450 2B4 in hepatic microsomes from phenobarbital-induced rabbits as well as the expressed enzyme. The basis for poor inactivation of P450 2B5 by PCP was determined to be the low maximal rate constant for this P450 2B form. N-Aralkylated 1-aminobenzotriazole derivatives were found to be potent inactivators of both P450 2B enzymes and to be much less selective than phencyclidine. These results demonstrate that one or more of the amino acid differences in P450 2B5 are critical to its substrate specificities and selective inactivation. Rabbits which express P450 2B5 have the potential to exhibit different hepatic biotransformation pathways in comparison with animals that lack this enzyme.This 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 [email protected] file replaced with corrected file November 2023
Maternal and professional identity change during the transition to motherhood
No full textBecoming a mother derails many women’s chances for career progression. One reason for this is that women leave organisations when they become mothers, or reduce their working hours. Another reason is that people within the organisation start to view them as less career-orientated as a result of being mothers. At the core of this issue is that who a woman is – her identity – is being redefined in the transition to motherhood, by herself and by those around her. But, little is known about how her professional identity develops during the transition to motherhood, or whether its development is related to her growing maternal identity. This paper, therefore, presents a systematic review of the literature concerning changes in maternal and professional identities, as well as the relationship between them. Based on the evidence, this review concludes that although the development of maternal identity has been well documented in the literature, little is known about how a woman’s professional identity develops, as she becomes a mother. Suggestions for further research and practice are discussed
Evidence-based Venous Thromboembolism Prophylaxis is Associated With a Six-fold Decrease in Numbers of Symptomatic Venous Thromboembolisms in Rehabilitation Inpatients
No full textWhen ENSO Reigns, It Pours: Climate Forecasts in Flood Planning
No full textRecent scientific and technical advances have increased the potential use of longterm seasonal climate forecasts for improving water resource management. This paper examines the role that forecasts, in particular those based on the El Nino-Southern Oscillation (ENSO) cycle, can play in flood planning in the Pacific Northwest. While strong evidence of an association between ENSO signals and flooding in the region exists, this association is open to more than one interpretation depending on: a) the metric used to test the strength of the association; b) the definition of critical flood events; c) site-specific features of watersheds; and d) the characteristics of flood management institutions. A better understanding and appreciation of such ambiguities, both institutional and statistical, is needed to facilitate the use of climate forecast information for flood planning and response.Flooding, Climate, ENSO, Water Resources Planning, Water Policy, Water Management
Four Decades of Cytochrome P450 2B Research: From Protein Adducts to Protein Structures and beyond
No full textThis article features selected findings from the senior author and colleagues dating back to 1978 and covering approximately three-fourths of the 60 years since the discovery of cytochrome P450. Considering the vast number of P450 enzymes in this amazing superfamily and their importance for so many fields of science and medicine, including drug design and development, drug therapy, environmental health, and biotechnology, a comprehensive review of even a single topic is daunting. To make a meaningful contribution to the 50th anniversary of Drug Metabolism and Disposition, we trace the development of the research in a single P450 laboratory through the eyes of seven individuals with different backgrounds, perspectives, and subsequent career trajectories. All co-authors are united in their fascination for the structural basis of mammalian P450 substrate and inhibitor selectivity and using such information to improve drug design and therapy. An underlying theme is how technological advances enable scientific discoveries that were impossible and even inconceivable to prior generations. The work performed spans the continuum from: 1) purification of P450 enzymes from animal tissues to purification of expressed human P450 enzymes and their site-directed mutants from bacteria; 2) inhibition, metabolism, and spectral studies to isothermal titration calorimetry, deuterium exchange mass spectrometry, and NMR; 3) homology models based on bacterial P450 X-ray crystal structures to rabbit and human P450 structures in complex with a wide variety of ligands. Our hope is that humanizing the scientific endeavor will encourage new generations of scientists to make fundamental new discoveries in the P450 field
Four Decades of Cytochrome P450 2B Research: From Protein Adducts to Protein Structures and Beyond.
No full textClick on the Resource Link to access the article (may not be free).This article features selected findings from the senior author and colleagues dating back to 1978 and covering approximately three-fourths of the 60 years since the discovery of cytochrome P450. Considering the vast number of P450 enzymes in this amazing superfamily and their importance for so many fields of science and medicine, including drug design and development, drug therapy, environmental health, and biotechnology, a comprehensive review of even a single topic is daunting. To make a meaningful contribution to the 50th anniversary of , we trace the development of the research in a single P450 laboratory through the eyes of seven individuals with different backgrounds, perspectives, and subsequent career trajectories. All co-authors are united in their fascination for the structural basis of mammalian P450 substrate and inhibitor selectivity and using such information to improve drug design and therapy. An underlying theme is how technological advances enable scientific discoveries that were impossible and even inconceivable to prior generations. The work performed spans the continuum from: 1) purification of P450 enzymes from animal tissues to purification of expressed human P450 enzymes and their site-directed mutants from bacteria; 2) inhibition, metabolism, and spectral studies to isothermal titration calorimetry, deuterium exchange mass spectrometry, and NMR; 3) homology models based on bacterial P450 X-ray crystal structures to rabbit and human P450 structures in complex with a wide variety of ligands. Our hope is that humanizing the scientific endeavor will encourage new generations of scientists to make fundamental new discoveries in the P450 field. SIGNIFICANCE STATEMENT: The manuscript summarizes four decades of work from Dr. James Halpert's laboratory, whose investigations have shaped the cytochrome P450 field, and provides insightful perspectives of the co-authors. This work will also inspire future drug metabolism scientists to make critical new discoveries in the cytochrome P450 field.Grant FundedR37 GM076343/GM/NIGMS NIH HHS/United StatesR01 CA204846/CA/NCI NIH HHS/United Stateshttps://doi.org/10.1124/dmd.122.00110
