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Influences of inducers and inhibitors of the microsomal monooxygenase system on the alkylating intensity of dimethylnitrosamine in mice

Einfluß von induktoren und inhibitoren des mikrosomalen monooxygenasesystems auf die alkylierungsintensität von dimethylnitrosamin bei mäusen

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  • Experimental Oncology
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Zusammenfassung

Bei unbehandelten oder mit Induktoren bzw. Inhibitoren der mikrosomalen Monooxygenase vorbehandelten männlichen NMRI Mäusen wurden fünf Stunden nach i.p.-Injektion von 14C-Dimethylnitrosamin (10 mg/kg) in den einzelnen Zellkompartimenten der Leber die gesamte und spezifische Radioaktivität von Proteinen, DNA und RNA bestimmt. Zur Differenzierung von Alkylierung und 14C1-Inkorporation wurden DNA und funktionsspezifische RNA-Formen durch Chromatographie über MAK, Oligo-(dt)-Zellulose und 3-ABBS isoliert und ihre Basen nach Hydrolyse durch Ionenaustausch-Chromatographie getrennt. Vorbehandlung mit den Induktoren Phenobarbital und 3-Methylcholanthren führte zur Erniedrigung der Alkylierungsraten, Vorbehandlung mit den Inhibitoren SKF 525 A und CFT 1201 zu ihrer Steigerung. Unspezifische Faktoren wie Unterschiede in Resorption und Bioverfügbarkeit von DMN, Veränderungen von Alkylierungskinetik oder Alkylierungsprofil konnten als Ursachen dieser Effekte ausgeschlossen werden. Unter der Voraussetzung, daß die oxidative Desalkylierung von DMN durch Induktoren und Inhibitoren der Monooxygenase in gleicher Weise beeinflußt wird wie andere cyt. P 450 abhängige N-Dimethylierungen, widersprechen die Ergebnisse dem allgemein angenommenen Aktivierungsmechanismus der Nitrosamine. Die Problematik der darüber mitgeteilten kontroversen Daten wird diskutiert.

Summary

Male mice were pretreated with various drugs, which are known either to induce or to inhibit cytochrome P 450 function. Five hours after the administration of 14C-dimethylnitrosamine (10 mg/kg) in pretreated and control mice, total and specific radioactivities of cellular macromolecules of the liver were determined. Various types of nucleic acids were extracted and hydrolyzed, and the bases and nucleotides separated by ion-exchange-chromatography. Radioactivity · resulting from incorporation and alkylation was measured. Pretreatment of mice with the inducers phenobarbital and 3-Methylcholanthrene decreased the alkylation rates, while administration of the inhibitors SKF 525 A and CFT 1201 caused an increase. These results appear to contradict the accepted activation mechanism of nitrosamines if DMN demethylation as catalyzed by cyt. P 450 is influenced in the same way as other cyt. P 450 dependent reactions.

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Abbreviations

DMN:

dimethylnitrosamine

PB:

phenobarbital

3-MC:

3-Methylcholanthrene

SKF 525 A:

2-diethylaminoethyl-2,2-diphenylvalerate HCl

CFT:

1201 2-diethylaminoethyl-2-phenyl-2-(2-propene)-4-penten-1-oate HCl

cyt. P 450:

cytchrome P 450

MAK:

Methylalbumin-Kieselguhr

3 ABBS:

3-aminobenzeneboronic acid

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Authors and Affiliations

  1. Abt. Molekulare Toxikologie, Institut für Biochemie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-6900, Heidelberg, Federal Republic of Germany

    K. E. Appel, M. Schwarz, R. Rickart & W. Kunz

  2. Institut für Toxikologie, Universität Tübingen, D-7400, Tübingen, Federal Republic of Germany

    K. E. Appel, M. Schwarz, R. Rickart & W. Kunz

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  1. K. E. Appel
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  2. M. Schwarz
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  3. R. Rickart
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  4. W. Kunz
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This work was supported by the Deutsche Forschungsgemeinschaft

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Appel, K.E., Schwarz, M., Rickart, R. et al. Influences of inducers and inhibitors of the microsomal monooxygenase system on the alkylating intensity of dimethylnitrosamine in mice. J Cancer Res Clin Oncol 94, 47–61 (1979). https://doi.org/10.1007/BF00405349

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  • DOI: https://doi.org/10.1007/BF00405349

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