Showing papers by "Jeroen Buters published in 2002"
TL;DR: DNA binding studies using embryonic fibroblasts isolated from these animals provided further evidence that P450 1B1-catalyzed formation of fjord region DB[a,l]PDE-DNA adducts is the critical step in DB[ a, l]P-mediated carcinogenesis in mice, and probably also in man.
Abstract: Metabolic activation, DNA binding, and tumorigenicity of the carcinogenic polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P) catalyzed by murine cytochrome P450 (P450) enzymes were investigated. DNA binding of DB[a,l]P in human mammary carcinoma MCF-7 and human P450-expressing Chinese hamster V79 cell lines was previously shown to occur preferentially with metabolically generated fjord region DB[a,l]P-11,12-dihydrodiol 13,14-epoxides (DB[a,l]PDE). To elucidate different capabilities of murine P450 1A1 and 1B1 for metabolic activation of DB[a,l]P, V79 cell cultures stably expressing P450s 1A1 or 1B1 from mice were exposed to 10 or 100 nM DB[a,l]P. Both cell lines transformed DB[a,l]P to DNA binding intermediates. As with V79 cells expressing the corresponding human P450 enzyme [Luch et al. (1998) Chem. Res. Toxicol. 11, 686-695], murine P450 1B1-catalyzed metabolism and DNA binding proceeded exclusively through generation of fjord region DB[a,l]PDE. In addition, only DB[a,l]PDE-derived DNA adducts were found in V79 cells expressing P450 1A1 from mice. This is in contrast to our recent findings with V79 cells expressing P450 1A1 from humans or rats which catalyzed the formation of both highly polar DNA adducts as well as nonpolar DB[a,l]PDE-DNA adducts. To establish the role of P450 1B1 in DB[a,l]P-induced tumor formation in vivo, we treated P450 1B1-null and wild-type mice intragastrically and monitored survival rates and appearance of neoplasias in various organs. All wild-type mice (n = 17) used in this study developed at least one tumor at one site (tumor rate of 100%). In contrast, 5 of 13 P450 1B1-null mice were observed to be free from any tumor (tumor rate of 62%). The organ sites of tumor formation and the dignity of tumors were different between wild-type and P450 1B1-null mice. Wild-type mice were diagnosed with both benign and malignant tumors of the ovaries, lymphoid tissues, as well as with skin and endometrial hyperplasias, whereas P450 1B1-null mice developed only lung adenomas and endometrial hyperplasias. DNA binding studies using embryonic fibroblasts isolated from these animals provided further evidence that P450 1B1-catalyzed formation of fjord region DB[a,l]PDE-DNA adducts is the critical step in DB[a,l]P-mediated carcinogenesis in mice, and probably also in man.
90 citations
TL;DR: It is suggested that an interspecies comparison is required for the metabolism of individual xenobiotics interacting with CYP1A2 prior to the use of mice models to predict its toxicity and/or pharmacological activity in man.
21 citations
TL;DR: Treatment of P450 1B1 knockout mice and DNA binding studies with fibroblasts isolated from these animals provided further evidence for the central role of P550 1A1-catalyzed formation of ( m )- anti -DB[ a,l ]PDE-DNA adducts in DB[ a-l ]P-induced carcinogenesis.
10 citations
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TL;DR: In der Ausenluft bestehen Interaktionen zwischen den Allergentragern (z. B. Pollen) und Luftschadstoffen, die u.a.
Abstract: Allergien und im speziellen hier atopieassoziierte Typ-I-Reaktionen sind klassische Umwelterkrankungen, wobei die auslosenden Substanzen (das sind die Allergene) grosteils bereits charakterisiert und in rekombinanter Form erhaltlich sind. Neben dieser Kausalkette, Allergen und Sensibilisierung gegenuber diesem Allergen, wirken Umwelteinflusse unterschiedlichster Art modulierend – verstarkend oder protektiv – auf die Allergieentwicklung ein. Dabei muss zwischen biogenen und anthropogenen Umweltfaktoren unterschieden werden. Unter den allergiefordernden Faktoren kommt im Innenraum dem Tabakrauch, in der Ausenluft der Exposition durch Verkehrsbelastung eine entscheidende Rolle zu. In der Ausenluft bestehen Interaktionen zwischen den Allergentragern (z. B. Pollen) und Luftschadstoffen, die u. U. zur weiteren Verstarkung allergischer Reaktionen, insbesondere in der Symptomverschlechterung, eine Rolle spielen. Durch den Klimawandel mit zunehmender globaler Erwarmung wird eine Veranderung der saisonalen Verteilung und weitere Haufung von allergischen Erkrankungen mit regional neuen bzw. veranderten Allergenen zu erwarten sein.