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Nato Multimedia Library - One of the best experts on this subject based on the ideXlab platform.

Jeanmarie Dupret - One of the best experts on this subject based on the ideXlab platform.

  • Effect of environmental substances on the activity of arylamine N-acetyltransferases.
    Current Drug Metabolism, 2008
    Co-Authors: Fernando Rodrigues-lima, Julien Dairou, Jeanmarie Dupret
    Abstract:

    Arylamine N-acetyltransferases (NAT) are xenobiotic-metabolizing enzymes responsible for the acetylation of many aromatic arylamine and heterocyclic amines, thereby playing an important role in both detoxification and activation of numerous drugs and carcinogens. Two closely related isoforms (NAT1 and NAT2) have been described in humans. NAT2 is mainly expressed in liver and gut, whereas NAT1 is found in a wide range of tissues. Interindividual variations in NAT genes have been shown to be a potential source of pharmacological and/or pathological susceptibility. In addition, there is now evidence that non genetic factors, such as substratedependent inhibition, drug interactions or cellular redox conditions may also contribute to NAT activity. The recent findings reviewed here provide possible mechanisms by which these environmental determinants may affect NAT activity. Interestingly, these data could contribute to the development of selective NAT inhibitors for the treatment of cancer and microbial diseases.

  • 3d model of human arylamine n acetyltransferase 2 structural basis of the slow acetylator phenotype of the r64q variant and analysis of the active site loop
    Biochemical and Biophysical Research Communications, 2002
    Co-Authors: Fernando Rodrigueslima, Jeanmarie Dupret
    Abstract:

    Abstract The human arylamine N -acetyltransferase NAT2 is responsible for the biotransformation of numerous arylamine drugs and carcinogens. A common polymorphism of the NAT2 gene has been associated with susceptibility to drug toxicity and various malignancies. In this study, we used the crystal structure of the Salmonella typhimurium NAT ( St NAT) to construct a high-quality model of a catalytic N-terminal region of NAT2 (residues 34–131). We show that this region has a similar structure in St NAT and the human isoforms NAT1 and NAT2. Comparison of the structures of these three molecules suggests that NATs have an active-site loop with a conserved structure, which is involved in substrate recognition. Our model is consistent with previous experimental data and provides the first plausible structural basis of the effects of a common genetic polymorphism (Arg 64 →Gln) on NAT2 activity.

David W. Hein - One of the best experts on this subject based on the ideXlab platform.

  • Human acetylator genotype: Relationship to colorectal cancer incidence and arylamine N-acetyltransferase expression in colon cytosol
    Archives of Toxicology, 1993
    Co-Authors: Jose W. Rodriguez, Ward G. Kirlin, Ronald J. Ferguson, Mark A. Doll, Kevin Gray, Timothy D. Rustan, Katherine Kemp, Paul Urso, David W. Hein
    Abstract:

    Polymorphic expression of arylamine N-acetyltransferase (EC 2.3.1.5) may be a differential risk factor in metabolic activation of arylamine carcinogens and susceptibility to cancers related to arylamine exposures. Human epidemiological studies suggest that rapid acetylator phenotype may be associated with higher incidences of colorectal cancer. We used restriction fragment length polymorphism analysis to determine acetylator genotypes of 44 subjects with colorectal cancer and 28 non-cancer subjects of similar ethnic background (i.e., approximately 25% Black and 75% White). The polymorphic N-acetyltransferase gene ( NAT2 ) was amplified by the polymerase chain reaction from DNA templates derived from human colons of colorectal and non-cancer subjects. No significant differences in NAT2 allelic frequencies (i.e., WT, M1, M2, M3 alleles) or in acetylator genotypes were found between the colorectal cancer and non-cancer groups. No significant differences in NAT2 allelic frequencies were observed between Whites and Blacks or between males and females. Cytosolic preparations from the human colons were tested for expression of arylamine N-acetyltransferase activity. Although N-acetyltransferase activity was expressed for each of the arylamines tested (i.e., p-aminobenzoic acid, 4-aminobiphenyl, 2-aminofluorene, β-naphthylamine), no correlation was observed between acetylator genotype and expression of human colon arylamine N-acetyltransferase activity. Similarly, no correlation was observed between subject age and expression of human colon arylamine N-acetyltransferase activity. These results suggest that arylamine N-acetyltransferase activity expressed in human colon is catalyzed predominantly by NAT1, an arylamine N-acetyltransferase that is not regulated by NAT2 acetylator genotype. The ability to determine acetylator genotype from DNA derived from human surgical samples should facilitate further epidemiological studies to assess the role of acetylator genotype in various cancers.

Fernando Rodrigueslima - One of the best experts on this subject based on the ideXlab platform.

  • 3d model of human arylamine n acetyltransferase 2 structural basis of the slow acetylator phenotype of the r64q variant and analysis of the active site loop
    Biochemical and Biophysical Research Communications, 2002
    Co-Authors: Fernando Rodrigueslima, Jeanmarie Dupret
    Abstract:

    Abstract The human arylamine N -acetyltransferase NAT2 is responsible for the biotransformation of numerous arylamine drugs and carcinogens. A common polymorphism of the NAT2 gene has been associated with susceptibility to drug toxicity and various malignancies. In this study, we used the crystal structure of the Salmonella typhimurium NAT ( St NAT) to construct a high-quality model of a catalytic N-terminal region of NAT2 (residues 34–131). We show that this region has a similar structure in St NAT and the human isoforms NAT1 and NAT2. Comparison of the structures of these three molecules suggests that NATs have an active-site loop with a conserved structure, which is involved in substrate recognition. Our model is consistent with previous experimental data and provides the first plausible structural basis of the effects of a common genetic polymorphism (Arg 64 →Gln) on NAT2 activity.

Paul Hooft - One of the best experts on this subject based on the ideXlab platform.

  • Land rush: American grand strategy, NATO enlargement, and European fragmentation
    International Politics, 2020
    Co-Authors: Paul Hooft
    Abstract:

    This article argues that NATO enlargement, while stabilizing Central and Eastern Europe, still undermined other aspects of European security over the long term. Throughout the 1990s and 2000s, US administrations pursued three ambitious policies: they expanded NATO, but also its geographic scope, and they ensured that no alternative European security architectures could compete with NATO. Through interviews with US officials, the article shows a preoccupation with instability in Europe and elsewhere, an institutional predisposition to maintaining the centrality of NATO, and a lack of constraints on US policies by Russia or Europe. In the end, these contradictory policies diluted European strategic cohesion and overburdened European militaries, while expanding the commitments inherent to the alliance.

  • land rush american grand strategy NATO enlargement and european fragmentation
    International Politics, 2020
    Co-Authors: Paul Hooft
    Abstract:

    This article argues that NATO enlargement, while stabilizing Central and Eastern Europe, still undermined other aspects of European security over the long term. Throughout the 1990s and 2000s, US administrations pursued three ambitious policies: they expanded NATO, but also its geographic scope, and they ensured that no alternative European security architectures could compete with NATO. Through interviews with US officials, the article shows a preoccupation with instability in Europe and elsewhere, an institutional predisposition to maintaining the centrality of NATO, and a lack of constraints on US policies by Russia or Europe. In the end, these contradictory policies diluted European strategic cohesion and overburdened European militaries, while expanding the commitments inherent to the alliance.