Problematika propojování informačních systémů

Příspěvek se zabývá problematikou propojování informačních systémů ve státní správě, popisem stávající situace a návrhů řešení. Řešení je navrhováno pouze v rovině IT, ostatní aspekty řešení (sociální a právní) nejsou řešeny.Article is focused to the area of interconnecting of public administration information systems, description of actual situation and drafts of possible ways. The draft is done only on IT level; other aspects (social and juristic) are not described

Studium metabolizmu kancerogenního o-anisidinu, jeho metabolitu N-(2-methoxyfenyl) hydroxylaminu a tvorby jejich aduktů s DNA

CHARLES UNIVERSITY IN PRAGUE FACULTY OF SCIENCE DEPARTMENT OF BIOCHEMISTRY Metabolism of and DNA Adduct Formation by Carcinogenic o-Anisidine and its Metabolite N-(2-Methoxyphenyl)hydroxylamine Summary of Ph.D. Thesis RNDr. Karel Naiman Supervisor: Prof. RNDr. Marie Stiborová, DrSc. PRAGUE 2010 Introduction - 2 - INTRODUCTION Aromatic amines are potent toxic or carcinogenic compounds, presenting a considerable danger to the human population (NTP, 1978; IARC, 1982; Garner et al., 1984). They are widely distributed environmental pollutants found in workplaces (e.g. in chemical industry), in emissions from diesel and gasoline engines and on the surface of ambient air particulate matter (NTP, 1978; IARC, 1982), where they add to local and regional pollution (car exhausts, technological spills). Their toxicity and carcinogenicity has been widely examined, but the knowledge in metabolism of several aromatic amines and their physiological effects in humans are still incomplete. This is also the case of o-anisidine. 2-Methoxyaniline (o-anisidine, Fig. 1) is a potent carcinogen, causing tumours of the urinary bladder in both genders of F344 rats and B6C3F1 mice (NTP, 1978; IARC, 1982). The International Agency for Research on Cancer (IARC) has classified o-anisidine as a group 2B carcinogen (IARC, 1982), which is...UNIVERZITA KARLOVA V PRAZE PŘÍRODOVĚDECKÁ FAKULTA KATEDRA BIOCHEMIE Studium metabolizmu kancerogenního o-anisidinu, jeho metabolitu N-(2-methoxyfenyl)hydroxylaminu a tvorby jejich aduktů s DNA Autoreferát dizertační práce RNDr. Karel Naiman Školitel: Prof. RNDr. Marie Stiborová, DrSc. PRAHA 2010 Úvod - 2 - ÚVOD Aromatické aminy patří mezi toxické a kancerogenní sloučeniny, které představují značný rizikový faktor pro člověka (NTP, 1978; IARC, 1982; Garner et al., 1984). Aromatické aminy jsou řazeny mezi všudypřítomné polutanty životního prostředí a jsou často využívány v průmyslových výrobách. Tyto sloučeniny jsou přítomné ve výfukových plynech a jsou též adsorbované na vzdušné prachové částice (NTP, 1978; IARC, 1982). Jejich toxické a kancerogenní působení bylo a je středem vědeckého zájmu, ale stále není zcela objasněn komplexní metabolizmus některých aromatických aminů spolu s jejich fyziologickým působením na lidský organismus. Tento fakt také platí pro o-anisidin. Proto je metabolizmus tohoto kancerogenu studován v předkládané dizertační práci. 2-Methoxyanilin (o-anisidin, obr. 1) je silným kancerogenem, způsobujícím nádory močového měchýře u obou pohlaví potkanů F344 a myší B6C3F1 (NTP, 1978; IARC, 1982). Mezinárodní agentura pro výzkum rakoviny (The International Agency for Research on Cancer; IARC)...Department of BiochemistryKatedra biochemieFaculty of SciencePřírodovědecká fakult

Genotoxic mechanisms for the carcinogenicity of the environmental pollutants and carcinogens o-anisidine and 2-nitroanisole follow from adducts generated by their metabolite N-(2-methoxyphenyl)-hydroxylamine with deoxyguanosine in DNA

An aromatic amine, o-anisidine (2-methoxyaniline) and its oxidative counterpart, 2-nitroanisole (2-methoxynitrobenzene), are the industrial and environmental pollutants causing tumors of the urinary bladder in rats and mice. Both carcinogens are activated to the same proximate carcinogenic metabolite, N-(2-methoxyphenyl)hydroxylamine, which spontaneously decomposes to nitrenium and/or carbenium ions responsible for formation of deoxyguanosine adducts in DNA in vitro and in vivo. In other words, generation of N-(2-methoxyphenyl)hydroxylamine is responsible for the genotoxic mechanisms of the o-anisidine and 2-nitroanisole carcinogenicity. Analogous enzymes of human and rat livers are capable of activating these carcinogens. Namely, human and rat cytochorme P4502E1 is the major enzyme oxidizing o-anisidine to N-(2-methoxyphenyl)hydroxylamine, while xanthine oxidase of both species reduces 2-nitroanisole to this metabolite. Likewise, O-demethylation of 2-nitroanisole, which is the detoxication pathway of its metabolism, is also catalyzed by the same human and rat enzyme, cytochorme P450 2E1. The results demonstrate that the rat is a suitable animal model mimicking the fate of both carcinogens in humans and suggest that both compounds are potential carcinogens also for humans

Cytochrome P450-mediated metabolism of N-(2-methoxyphenyl)-hydroxylamine, a human metabolite of the environmental pollutants and carcinogens o-anisidine and o-nitroanisole

N-(2-methoxyphenyl)hydroxylamine is a human metabolite of the industrial and environmental pollutants and bladder carcinogens 2-methoxyaniline (o-anisidine) and 2-methoxynitrobenzene (o-nitroanisole). Here, we investigated the ability of hepatic microsomes from rat and rabbit to metabolize this reactive compound. We found that N-(2-methoxyphenyl)hydroxylamine is metabolized by microsomes of both species mainly to o-aminophenol and a parent carcinogen, o-anisidine, whereas 2-methoxynitrosobenzene (o-nitrosoanisole) is formed as a minor metabolite. Another N-(2-methoxyphenyl)hydroxylamine metabolite, the exact structure of which has not been identified as yet, was generated by hepatic microsomes of rabbits, but its formation by those of rats was negligible. To evaluate the role of rat hepatic microsomal cytochromes P450 (CYP) in N-(2-methoxyphenyl)hydroxylamine metabolism, we investigated the modulation of its metabolism by specific inducers of these enzymes. The results of this study show that rat hepatic CYPs of a 1A subfamily and, to a lesser extent those of a 2B subfamily, catalyze N-(2-methoxyphenyl)hydroxylamine conversion to form both its reductive metabolite, o-anisidine, and o-aminophenol. CYP2E1 is the most efficient enzyme catalyzing conversion of N-(2-methoxyphenyl)hydroxylamine to o-aminophenol

Metabolism of and DNA Adduct Formation by Carcinogenic o-Anisidine and its Metabolite N-(2-Methoxyphenyl) hydroxylamine

CHARLES UNIVERSITY IN PRAGUE FACULTY OF SCIENCE DEPARTMENT OF BIOCHEMISTRY Metabolism of and DNA Adduct Formation by Carcinogenic o-Anisidine and its Metabolite N-(2-Methoxyphenyl)hydroxylamine Summary of Ph.D. Thesis RNDr. Karel Naiman Supervisor: Prof. RNDr. Marie Stiborová, DrSc. PRAGUE 2010 Introduction - 2 - INTRODUCTION Aromatic amines are potent toxic or carcinogenic compounds, presenting a considerable danger to the human population (NTP, 1978; IARC, 1982; Garner et al., 1984). They are widely distributed environmental pollutants found in workplaces (e.g. in chemical industry), in emissions from diesel and gasoline engines and on the surface of ambient air particulate matter (NTP, 1978; IARC, 1982), where they add to local and regional pollution (car exhausts, technological spills). Their toxicity and carcinogenicity has been widely examined, but the knowledge in metabolism of several aromatic amines and their physiological effects in humans are still incomplete. This is also the case of o-anisidine. 2-Methoxyaniline (o-anisidine, Fig. 1) is a potent carcinogen, causing tumours of the urinary bladder in both genders of F344 rats and B6C3F1 mice (NTP, 1978; IARC, 1982). The International Agency for Research on Cancer (IARC) has classified o-anisidine as a group 2B carcinogen (IARC, 1982), which is..

Study on DNA adducts formation by carcinogenic o-anisidine

Department of BiochemistryKatedra biochemiePřírodovědecká fakultaFaculty of Scienc

Study on DNA adducts formation by carcinogenic o-anisidine

Department of BiochemistryKatedra biochemiePřírodovědecká fakultaFaculty of Scienc

Study on DNA adducts formation by carcinogenic o-anisidine

Department of BiochemistryKatedra biochemieFaculty of SciencePřírodovědecká fakult

A defect in homologous recombination leads to increased translesion synthesis in E. coli.

International audienceDNA damage tolerance pathways allow cells to duplicate their genomes despite the presence of replication blocking lesions. Cells possess two major tolerance strategies, namely translesion synthesis (TLS) and homology directed gap repair (HDGR). TLS pathways involve specialized DNA polymerases that are able to synthesize past DNA lesions with an intrinsic risk of causing point mutations. In contrast, HDGR pathways are essentially error-free as they rely on the recovery of missing information from the sister chromatid by RecA-mediated homologous recombination. We have investigated the genetic control of pathway choice between TLS and HDGR in vivo in Escherichia coli In a strain with wild type RecA activity, the extent of TLS across replication blocking lesions is generally low while HDGR is used extensively. Interestingly, recA alleles that are partially impaired in D-loop formation confer a decrease in HDGR and a concomitant increase in TLS. Thus, partial defect of RecA's capacity to invade the homologous sister chromatid increases the lifetime of the ssDNA.RecA filament, i.e. the 'SOS signal'. This increase favors TLS by increasing both the TLS polymerase concentration and the lifetime of the TLS substrate, before it becomes sequestered by homologous recombination. In conclusion, the pathway choice between error-prone TLS and error-free HDGR is controlled by the efficiency of homologous recombination