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Imagining modernity in the Uganda Prisons Service, 1945-1979Bruce-Lockhart, Katherine deVries January 2017 (has links)
This dissertation is a social history of the Uganda Prisons Service in the late colonial and early post-colonial periods. Focusing particularly on prison officers, it advances four key arguments. Firstly, it argues that global visions of the prison were crucial in shaping the Service’s development, its institutional culture, and the professional identities of its personnel. From the late colonial period onwards, this vision was anchored on notions of penal welfarism, which positioned the prison as a centre of rehabilitation, staffed by professionals who possessed technical expertise. Secondly, the penal welfare model was combined with an emphasis on the prison’s role as a driver of economic development and a source of public revenue – features that were seen as compatible with penal modernity. Thirdly, this vision of the prison gave the Service a particular imaginative capital, which prison officers used as an important resource. It provided them with a common set of principles and norms through which to define their professional role. Senior officers adopted it with alacrity, pursuing further professionalization through engagement with transnational penal reform networks. Others summoned it as a source of claim-making, using it to call on the state to provide them with greater benefits and treat them as respectable public servants. Finally, visions of penal modernity and professionalism were contested throughout the periods under study, leading officers to engage in boundary work. Officers were regularly defining their role in relation to other spaces of incarceration, such as local government prisons and informal detention sites. With the take-over of Idi Amin in 1971 and the militarization of the state, prison officers’ professional identities were profoundly challenged, but also became particularly important, providing them with a conceptual boundary that at least partially demarcated them from Amin’s regime. Ultimately, the case of the Uganda Prisons Service reminds us of the importance of studying prisons beyond their coercive capacities, paying attention to how such institutions became the focal point of debates over modernity, authority, and professionalism. More broadly, this study challenges the narrative of failure that has dominated popular and scholarly portrayals of state institutions on the African continent, rejecting generic depictions of the postcolony as a site of chaos and disorder.
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Stabilizace epoxidových systémů v povrchových ochranných nátěrech / Stabilizing epoxide systems in surface protective varnishesŠvardala, Daniel January 2021 (has links)
The diploma thesis describes the influence of humid conditions on the curing of epoxy resins by multifunctional amines. The aim of the experimental part was the identification of degradation products and their quantification, as well as the determination of the influence of humid conditions on the degree of hardening, modulus of elasticity, and flexural strength. Another goal was to optimize the formulation of the reactive mixture for the preparation of epoxy resin with lower susceptibility to carbamate bloom. The degradation products were evaluated by determining the mechanical properties by bending test according to the standard ČSN EN 179-1. The degree of hardening was monitored through temperature modulated differential scanning calorimetry (TMDSC). Degradation products were identified by Fourier transform infrared spectroscopy (FTIR) and quantified by UV-VIS spectroscopy. The morphology of the surface layer was monitored by confocal laser scanning microscopy (CLSM). The dependence of the relative humidity of the environment on the curing process of the epoxy resin and its resulting mechanical properties was determined. Based on the analyzes, a modification of the formulation for the suppression of spurious carbamate during the curing of the epoxy matrix was designed and experimentally verified.
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A modern reformist movement among the Sunni ʻulamâʹ in East Africa /Salim, Swalha. January 1985 (has links)
No description available.
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Der Mufti von Jerusalem und die Nationalsozialisten : eine politische Biographie Amin el-HusseinisGensicke, Klaus January 2007 (has links)
Zugl.: Berlin, Freie Univ., Diss., 1987 u.d.T.: Gensicke, Klaus: Der Mufti von Jerusalem, Amin el-Husseini, und die Nationalsozialisten
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A Christian ethical approach to economic globalization : an alternative to Samir Amin's humanism and Hans Küng's global ethic and its implications in the Burundian context.Ntibagirirwa, Symphorien. January 2001 (has links)
Economic globalization is a relatively recent phenomenon which has become familiar nowadays both in theory and practice. By definition, economic globalization is a transnational phenomenon characteristic of the post-industrial era and whose driving forces are respectively the recent technological innovations (as its engine), media of communication (information technology) as its facilitator, and political liberalism as its underlying political ideology, particularly after the collapse of doctrinaire socialism and the disintegration of the Soviet Union and its satellites. The phenomenon of economic globalization is ambiguous. It is a symbol of promise for some, yet a symbol of threat and alienation for others. It has both positive and negative effects. In effect, we can appreciate the dividends of economic globalization as they are evident in the growth of international trade, a tendency to universalize liberal democracy as a result of the failure of socialism and its command economy, an apparent international solidarity, economic prosperity as well as the triumph of the market economy. On the negative side, we cannot be blind to the obvious growing marginalization of the poor countries and the poor within countries, the demise of the nation-state coupled with social and political instability, inequality and social injustices between and within countries, ecological degradation and moral decadence due to blind interests in the market and maximization of profit. However, the negative effects seem to weigh more than the positive ones. This raises the question of how to respond to economic globalization. Two responses are analysed and critiqued in this dissertation. The first response, that of Samir Amin, comes from a Neo-Marxist perspective. Amin suggests a reversal of economic globalization altogether. This reversal consists in the reconsideration of the international socialism whereby each state should be allowed to negotiate the terms of interdependence with other states (poly-centrism). The second response is that of Hans Kung, who suggests a global ethic that could give economic globalization a human face. This economy with a human face is an "Aristotelian mean" economy; a kind of economy which is between the welfare state and neo-capitalism. The content of this global ethic supposed to underlie this economy is a set of values drawn from most of the religious traditions of the world. My contention is that neither Amin's international socialism nor Kung's global ethic constitute a satisfactory challenge to the power of the market and profit that are the main motive of economic globalization. Amin's international socialism is unrealistic and unreliable, particularly in this time when Marxist socialism has failed economically and has shown itself unpopular and unhelpful in practice. Kung's idea of global ethic is a powerful suggestion. Nevertheless it lacks a conceptual foundation which would redeem it from the risk of being a mere ethical contract. This conceptual framework should be an alternative to that of the Smithian homo oeconomicus that informs today's economy. The present economic order evolves around the neoclassical narrow understanding of the human being as homo oeconomicus. Thus, if we are to provide an ethic for the phenomenon of economic globalization, we have to build it on a concept that goes beyond the economic man. Such a concept should be an answer to the following double question: What/who are we, and how should we live given what/who we are? The concept that seems to best answer these questions is the concept of imago Dei as relational, central to the Judeo-Christian anthropology. The social, political and ecological implications of imago Dei as relational should help us to reconstruct the human community as the context of moral values, empower the state as the natural society that can work in partnership with the Church as the family of God, and finally consider those values that can help us to consider the enviromnent as something that is not at the disposal of human domination and overexploitation. The ethic of imago Dei as reIational is applied to the Burundian context as its testing ground. With the ethic of imago Dei as relational, the growth of the international trade should benefit the poor instead of marginalizing them, political liberalism would not lead to disorder which the profit seekers exploit to the detriment of the state, solidarity would imply equality and social justice as well as environmental care, and moral values would recover their priority over market judgment in which everything is referred to in terms of commodity. The implications of such an ordering are the following: the humanization of foreign aid and humanitarian service, the orientation of economic investment towards human promotion and not only for profit, a shift from self-enrichment minded political leadership to a leadership open to socio-economic empowerment of the poor as well as environmental care. / Thesis (M.A.)-University of Natal, Pietermaritzburg, 2001.
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An Efficient Rechargeable Aluminium–Amine Battery Working Under Quaternization ChemistryWang, Gang, Dmitrieva, Evgenia, Kohn, Benjamin, Scheler, Ulrich, Liu, Yannan, Tkachova, Valeriya, Yang, Lin, Fu, Yubin, Ma, Ji, Zhang, Panpan, Wang, Faxing, Ge, Jin, Feng, Xinliang 19 April 2024 (has links)
Rechargeable aluminium (Al) batteries (RABs) have long-been pursued due to the high sustainability and three-electron-transfer properties of Al metal. However, limited redox chemistry is available for rechargeable Al batteries, which restricts the exploration of cathode materials. Herein, we demonstrate an efficient Al–amine battery based on a quaternization reaction, in which nitrogen (radical) cations (R3N*+ or R4N+) are formed to store the anionic Al complex. The reactive aromatic amine molecules further oligomerize during cycling, inhibiting amine dissolution into the electrolyte. Consequently, the constructed Al–amine battery exhibits a high reversible capacity of 135 mAhg1 along with a superior cycling life (4000 cycles), fast charge capability and a high energy efficiency of 94.2%. Moreover, the Al–amine battery shows excellent stability against selfdischarge, far beyond conventional Al–graphite batteries. Our findings pave an avenue to advance the chemistry of RABs and thus battery performance.
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L'Ouganda du général Idi Amin Dada de 1971-1979 : une étude comparative des approches du London Times et du GuardianBernier-Duchaussoy, Maryse 06 March 2024 (has links)
Le mémoire qui suit a pour objectif de faire ressortir les grandes lignes du traitement de la prise de pouvoir d’Amin, de la crise de la déportation des Asiatiques ainsi que de la rupture des liens diplomatiques entre la Grande-Bretagne et l’Ouganda telles que vues par le London Times et le Guardian. Il s’attardera également sur les divergences et les convergences entre les deux médias. Dans la mesure où elles sont assez distinctes pour représenter des approches à part entière, elle essaiera d’identifier les éléments qui influencent/structurent ces différentes approches en référence aux thèmes mentionnés auparavant.
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A influência do D-limoneno como promotor de absorção de ácido 5-aminolevulínico para Terapia Fotodinâmica do câncer de pele: avaliação in vitro e in vivo da permeação e retenção cutâneas / D-limonene influence in the cutaneous penetration enhancer for 5-aminolevulinic acid in photodynamic therapy of skin cancer: in vitro and in vivo skin permeation and retention studies.Bertolini, Wagner Luiz Heleno Marcus 27 April 2009 (has links)
BERTOLINI, WAGNER L. H. M. A influência do D-limoneno como promotor de absorção do ácido 5-aminolevulínico para Terapia Fotodinâmica do câncer de pele: avaliação in vitro e in vivo da permeação e retenção cutâneas. 2009 118f. Tese (Doutorado). Faculdade de Ciências Farmacêuticas de Ribeirão Preto Preto Universidade de São Paulo, Ribeirão Preto, 2009. O câncer é a segunda doença principal do planeta, muito próximo de se tornar a mais incidente. Os tratamentos tradicionais do câncer, tais como cirurgia, radioterapia e quimioterapia apresentam severos efeitos colaterais ao paciente devido à citotoxicidade que podem causar às células normais, além das cancerosas. Objetivando minimizar estes efeitos indesejáveis pesquisadores de diversas áreas afins vislumbram novas técnicas, novos tipos e formas de tratamentos que apresentem um melhor perfil terapêutico; que possam agir de forma mais seletiva contra as células cancerosas, minorando os efeitos indesejáveis em relação às células saudáveis. Dentre as técnicas pesquisadas destaca-se a Terapia Fotodinâmica (TFD). Esta é uma técnica de tratamento nova e promissora. A técnica do tratamento consiste em aplicar, no tecido alvo, substâncias fotossensibilizantes, posteriormente ativadas com luz de comprimentos de onda específicos, com a finalidade de produzir destruição celular, por meio da ação de produtos citotóxicos fotoativados. Destaca-se a seletividade apresentada pela técnica, que deve ser reconhecida como uma das vantagens entre as técnicas empregadas no tratamento do câncer. O presente trabalho objetiva verificar a influência do D-limoneno como promotor de permeação do ácido 5-aminolevulínico (5-ALA) em aplicação tópica. Isto visa aumentar a permeação do 5-ALA quando aplicado topicamente. O 5-ALA é convertido a protoporfirina-IX (PpIX) pela via do ciclo Heme. Esta é um potente agente fotossensibilizador endógeno. O interesse no uso deste promotor foi aumentar a taxa de penetração do 5-ALA, possibilitando a permeação de maiores quantidades do fármaco em questão. Para isto foram realizados estudos de permeação in vitro do 5-ALA, em concentração de 1% (p/p) utilizando-se formulações (emulsões O/A) com diferentes concentrações do promotor D-limoneno (0, 5, 10, 20 e 30%), (p/p). Observou-se que o fluxo in vitro do 5-ALA através da pele de orelha de porco aumentou para todas as formulações empregadas quando comparado ao controle, sem D-limoneno, para um período de estudo de 12h. A retenção no estrato córneo e na [epiderme + derme] apresentou aumento significativo, evidenciando, assim, um efeito eficiente do D-limoneno como promotor. Experimentos in vivo foram conduzidos em camundongos objetivando a análise do efeito da formulação na produção e acúmulo de PpIX na pele. Observou-se que o D-limoneno aumentou significantemente a quantidade de PpIX extraída da pele. Os resultados in vitro e in vivo mostraram o potencial do D-limoneno como promotor de absorção cutânea para o 5-ALA para a TFD tópica do cancer de pele. / BERTOLINI, WAGNER L. H. M. D-limonene influence in the cutaneous penetration enhancer for 5-aminolevulinic acid in photodynamic therapy of skin cancer: in vitro and in vivo skin permeation and retention studies. 2009 118f. Thesis (Doctoral). Faculdade de Ciências Farmacêuticas de Ribeirão Preto Preto Universidade de São Paulo, Ribeirão Preto, 2009. The topical administration of 5-ALA has been distinguished on skin cancer photodynamic therapy (PDT) because of its efficiency in the treatment of tumors and the reduced phototoxic collateral effects. However, this effectiveness is limited by its low penetration in the skin. A proposal to optimize the 5-ALA penetration in the skin is the use of cutaneous penetration enhancers, which seek to alter the cutaneous barrier for many bioactive molecules. The aim of this work was the pharmaceutical development of formulations containing D-limonene as a cutaneous penetration enhancer, seeking the increase of the cutaneous penetration of 5-ALA for skin cancer PDT. The in vitro flux of 5-ALA present in 1% (w/w) from different formulations containing D-limonene (20 e 30% w/w) was significantly increased after 12 hours of experiment, in comparison with formulations without D-limonene, mainly for the formulations containing 20% and 30% of D-limonene with 1% of 5-ALA (1,45 and 2,01 times, respectively). The stratum corneum (SC) and [epidermis + dermis] without SC retention were also significantly increased, showing an enhancer effect of the promoter. In addition, in vivo experiments were accomplished in mice, with the purpose of analyzing the formulation effect on the PpIX production and accumulation in the skin. It was observed that the penetration enhancer\'s presence significantly increased the amount of PpIX extracted from the skin. Both in vitro and in vivo results showed the potentiality of the formulations containing D-limonene as a cutaneous penetration enhancer for 5-ALA delivery on the skin cancer PDT.
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Engineering Cell-free Protein Synthesis Technology for Codon Reassignment, Biotherapeutics Production using Just-add-Water System, and Biosensing Endocrine Disrupting CompoundsSalehi, Sayed Mohammad 01 March 2017 (has links)
Cell-free protein synthesis is an emerging technology that has many applications. The open nature of this system makes it a compelling technology that can be manipulated to answer many needs that are unavailable in other systems. This dissertation reports on engineering this technology for: 1) sense codon emancipation for incorporation of multiple unnatural amino acids; 2) expressing a hard-to-express anticancer biotherapeutic and introducing a just-add-water system; 3) a biosensing ligand that interacts with nuclear hormone receptors. Emancipating sense codons toward a minimized genetic code is of significant interest to science and engineering. A promising approach to sense codon emancipation is the targeted in vitro removal of native tRNA. Here we introduce a new in-vitro or "cell-free" approach to emancipate sense codons via efficient and affordable degradation of endogenous tRNA using RNase-coated superparamagnetic beads. The presented method removes greater than 99% of tRNA in cell lysates, while preserving cell-free protein synthesis activity. The resulting tRNA-depleted lysate is compatible with in vitro-transcribed synthetic tRNA for the production of peptides and proteins. Biotherapeutics have many promising applications, such as anti-cancer treatments, immune suppression, and vaccines. However, due to their biological nature, some biotherapeutics can be challenging to rapidly express and screen for activity through traditional recombinant methods. In this work, we demonstrate the use of cell-free systems for the expression and direct screening of the difficult-to-express cytotoxic protein onconase. Using cell-free systems, onconase can be rapidly expressed in soluble, active form. Furthermore, the open nature of the reaction environment allows for direct and immediate downstream characterization without the need of purification. Also, we report the ability of a "just-add-water" lyophilized cell-fee system to produce onconase. Here we introduce a Rapid Adaptable Portable In-vitro Detection biosensor platform (RAPID) for detecting ligands that interact with nuclear hormone receptors (NHRs). The biosensor is based on an engineered, allosterically-activated fusion protein, which contains the ligand binding domain from a target NHR. The presented RAPID biosensor platform is significantly faster and less labor intensive than commonly available technologies, making it a promising tool for detecting environmental EDC contamination and screening potential NHR-targeted pharmaceuticals.
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Konstruktion und Charakterisierung transgener Mauslinien für humane Sulfotransferasen als Modellsysteme für eine SULT-vermittelte metabolische Aktivierung / Construction and characterisation of transgenic mouse lines for human sulfotransferases as model systems for a SULT-mediated metabolic activationDobbernack, Gisela January 2008 (has links)
Die Enzyme der Sulfotransferase-Gensuperfamilie (SULT) konjugieren nukleophile Gruppen von kleinen endogenen Verbindungen und Fremdstoffen mit der negativ geladenen Sulfo-Gruppe. Dadurch wird die Polarität dieser Verbindungen erhöht, ihre passive Permeation von Zellmembranen verhindert und somit ihre Ausscheidung erleichtert. Jedoch stellt die Sulfo-Gruppe in bestimmten chemischen Verbindungen eine gute Abgangsgruppen dar. Aus der Spaltung resultierende Carbenium- oder Nitreniumionen können mit DNA oder anderen zellulären Nukleophilen reagieren. In Testsystemen für Mutagenität wurden zahlreiche Verbindungen, darunter Nahrungsinhaltsstoffe und Umweltkontaminanten, durch SULT zu Mutagenen aktiviert. Dabei zeigten sich zum einen eine ausgeprägte Substratspezifität selbst orthologer SULT-Formen unterschiedlicher Spezies und zum anderen Interspezies-Unterschiede in der SULT-Gewebeverteilung. Daher könnten sich die Zielgewebe einer SULT-induzierten Krebsentstehung bei Mensch und Nager unterscheiden.
Um die Beteiligung von humanen SULT an der Bioaktivierung von Fremdstoffen im Tiermodell untersuchen zu können, wurden transgene Mauslinien für den Cluster der humanen SULT1A1- und -1A2-Gene sowie für die humane SULT1B1 generiert. Zur Herstellung der transgenen Linien wurden große genomische Konstrukte verwendet, die die SULT-Gene sowie – zum Erreichen einer der Humansituation entsprechenden Gewebeverteilung der Proteinexpression – deren potentielle regulatorische Sequenzen enthielten.
Es wurden je drei transgene Linien für hSULT1A1/hSULT1A2 und drei transgene Linien für hSULT1B1 etabliert. Die Expression der humanen Proteine konnte in allen Linien gezeigt werden und fünf der sechs Linien konnten zur Homozygotie bezüglich der Transgene gezüchtet werden. In der molekularbiologischen Charakterisierung der transgenen Linien wurde der chromosomale Integrationsort der Konstrukte bestimmt und die Kopienzahl pro Genom untersucht. Mit Ausnahme einer hSULT1A1/hSULT1A2-transgenen Linie, bei der Kopien des Konstrukts in zwei unterschiedliche Chromosomen integriert vorliegen, wiesen alle Linien nur einen Transgen-Integrationsort auf. Die Untersuchung der Transgen-Kopienzahl ergab, dass die Mauslinien zwischen einer und etwa 20 Kopien des Transgen-Konstrukts pro Genom trugen. In der proteinbiochemischen Charakterisierung wurde gezeigt, dass die transgenen Linien die humanen Proteine mit einer weitgehend der des Menschen entsprechenden Gewebeverteilung exprimieren. Die Intensität der im Immunblot nachgewiesenen Expression korrelierte mit der Kopienzahl der Transgene. Die zelluläre und subzelluläre Verteilung der Transgen-Expression wurden bei einer der hSULT1A1/hSULT1A2-transgenen Linien in Leber, Niere, Lunge, Pankreas, Dünndarm und Kolon und bei einer der hSULT1B1-transgenen Linien im Kolon untersucht. Sie stimmte ebenfalls mit der Verteilung der entsprechenden SULT-Formen im Menschen überein.
Da sich die erzeugten transgenen Linien aufgrund ihrer mit dem Menschen vergleichbaren Gewebeverteilung der SULT-Expression als Modellsystem zur Untersuchung der menschlichen SULT-vermittelten metabolischen Aktivierung eigneten, wurde eine der hSULT1A1/hSULT1A2-transgenen Linien für zwei erste toxikologische Untersuchungen eingesetzt. Den Mäusen wurden chemische Verbindungen verabreicht, für die in in-vitro-Versuchen eine hSULT1A1/hSULT1A2-vermittelte Bioaktivierung zu Mutagenen gezeigt worden war. In beiden Untersuchungen wurde die Gewebeverteilung der entstandenen DNA-Addukte als Endpunkt einer gewebespezifischen genotoxischen Wirkung ermittelt. In der ersten Untersuchung wurden 90 mg/kg Körpergewicht 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridin – ein in gebratenem Fleisch gebildetes heterozyklisches aromatisches Amin – transgenen sowie Wildtyp-Mäusen oral verabreicht. Acht Stunden nach Applikation wiesen die transgenen Mäuse signifikant höhere Adduktniveaus als die Wildtyp-Mäuse in Leber, Lunge, Niere, Milz und Kolon auf. In der Leber der transgen Mäuse war das Adduktniveau 17fach höher als in der Leber der Wildtyp-Mäuse. Die Leber war bei den transgenen Tieren das Organ mit dem höchsten, bei den Wildtyp-Tieren hingegen mit dem niedrigsten DNA-Adduktniveau. In der zweiten Untersuchung (Pilotstudie mit geringer Tierzahl) wurde transgenen und Wildtyp-Mäusen 19 mg/kg Körpergewicht des polyzyklischen aromatischen Kohlenwasserstoffs 1-Hydroxymethylpyren – ein Metabolit der Nahrungs- und Umweltkontaminante 1-Methylpyren – intraperitoneal verabreicht. Nach 30 Minuten wurden, verglichen mit den Wildtyp-Mäusen, bis zu 25fach erhöhte Adduktniveaus bei den transgenen Mäusen in Leber, Niere, Lunge und Jejunum nachgewiesen. Somit konnte anhand einer in dieser Arbeit generierten transgenen Mauslinie erstmals gezeigt werden, dass die Expression der humanen SULT1A1/hSULT1A2 tatsächlich sowohl auf die Stärke als auch die Zielgewebe der DNA-Adduktbildung in vivo eine Auswirkung hat. / The enzymes of the sulfotransferase gene superfamily (SULT) conjugate nucleophilic groups of small endogenous compounds and xenobiotics with the negatively charged sulfo group. Thus, the polarity of the compounds is increased, their passive permeation of cell membranes is hindered and their excretion facilitated. The sulfate groups, however, form a good leaving group in certain chemical linkages due to their electron-withdrawing characteristics. Carbenium or nitrenium ions resulting from a spontaneous cleavage may react with DNA and other cellular nucleophiles. In test systems for mutagenicity, a large amount of compounds including ingredients of nutrition and environmental contaminants were activated to mutagens by SULT. A pronounced substrate specificity even of orthologous SULT forms of different species was evidenced. Also, the tissue distribution of SULT exhibited pronounced interspecies differences. The target tissues of a SULT induced carcinogenesis might thus be different in humans and rodents.
To investigate the involvement of human SULT in the bioactivation of xenobiotics in an animal model, transgenic mouse lines for the human SULT1A1- and -1A2 gene cluster as well as for human SULT1B1 were generated. For the construction of the transgenic lines, large genomic constructs were used, containing the SULT genes plus their potential regulatory sequences to cause a tissue distribution of protein expression corresponding to the situation in humans. Three transgenic lines for hSULT1A1/hSULT1A2 and three transgenic lines for hSULT1B1 were established. The expression of the human proteins could be shown for all lines and except for one line, all could be bred to transgene homozygosity. By molecular biological characterization of the transgenic lines, the chromosomal integration locus of the constructs was identified and the copy number per genome was investigated. With the exception of one hSULT1A1/hSULT1A2 transgenic line, where the construct had integrated into two different chromosomes, all lines exhibited just one transgene integration locus. By investigating the transgene copy number it was deduced that the mouse lines carry between one and 20 copies of the transgene construct per genome. The protein biochemical characterization showed that the transgenic mouse lines express the human proteins with a tissue distribution largely similar to the distribution in humans. The intensity of the proteins detected by immunoblotting correlated with the copy number of the transgenes. The cellular and subcellular distribution of the transgene expression was investigated for one of the hSULT1A1/1A2 transgenic lines in liver, kidney, lung, pancreas, small intestine and colon and for one of the hSULT1B1 transgenic lines in colon. It also accorded with the distribution of the respective SULT in humans.
Owing to the similarity of transgene expression to the corresponding human tissue distribution, the transgenic lines were considered suitable as model systems for the investigation of the human SULT-mediated metabolic activation. One of the hSULT1A1/hSULT1A2 transgenic lines was used in two first toxicological investigations with chemical compounds for which in vitro experiments had demonstrated a hSULT1A1/hSULT1A2 mediated bioactivation. In both investigations, the tissue distribution of the resulting DNA adducts was determined as an end point for a tissue-specific genotoxic effect. For the first investigation, 90 mg/kg bodyweight of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine – a heterocyclic amine formed in cooked meat – were orally administered to transgenic and wild type mice. Eight hours after application, the transgenic mice exhibited significantly higher adduct levels than the wild type controls in liver, lung, kidney, spleen and colon. The adduct level in the liver of the transgenic mice exceeded that in the wild type liver by a factor of 17. Furthermore, the liver was the organ with the highest adduct level in the transgenic mice and with the lowest adduct level in the wild type mice. For the second investigation (a pilot study with few animals), 19 mg/kg bodyweight of the polycyclic aromatic hydrocarbon 1-hydroxymethylpyrene – a metabolite of the nutritional and environmental contaminant 1-methylpyrene – were administered intraperitoneally to transgenic and wild type mice. After 30 minutes, up to 25 fold higher adduct levels compared to the wild type were detected in liver, kidney, lung and jejunum of the transgenic mice. Thus, by means of one of the transgenic mouse line generated in this thesis, it could be shown for the first time that the expression of human SULT1A1/SULT1A2 has in fact an impact on the strength as well as on the target tissue of DNA-adduct generation in vivo.
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