Summary
Liver RNA was extracted from NMRI-mice 12 hours after i.p. applikation of 14C-dimethylnitrosamine. Column chromatography and density gradient centrifugation was used for the isolation and characterization of the different RNA species.
The RNA fractions methylated by 14C-dimethylnitrosamine were not identical to the methylated RNA species naturally occurring which are only slightly labelled. The highest incorporation of label is found in high-molecular RNA fractions. The radioactivity profile of these fractions corresponds to that of highly labelled RNA pulse labelled with 14C-orotic acid. Thus newly synthesized D-RNA and R-RNA are mainly alkylated. The methylation of all RNA species mainly that of the newly synthesized RNA, is due mostly to the formation of 7-methylguanin. The incorporation through the Cl-pool plays only a secondary role. The methylation of the guanine of the m-RNA leads to a disaggregation of polysomes and is surely the basis of the cytotoxic effects of nitrosamines. The causal relationship to the carcinogenic action is discussed.
Zusammenfassung
Bei NMRI-Mäusen wurde 12 Std nach i.p. Applikation von 14C-Dimethylnitrosamin die Leber-RNS extrahiert. Die Isolierung und Charakterisierung der RNS-Formen erfolgte durch Säulenchromatographie und Dichtegradientenzentrifugation.
Es wurde gefunden, daß die durch 14C-Dimethylnitrosamin methylierten RNS-Fraktionen nicht identisch mit den physiologisch methylierten RNS-Formen sind. Diese sind zwar auch geringfügig markiert, einen wesentlich stärkeren 14C-Einbau zeigen jedoch höhermolekulare RNS-Fraktionen; ihr Aktivitätsprofil entspricht dem der schnellmarkierten RNS nach Kurzzeitpulsmarkierung mit 14C-Orotsäure. Demnach werden vorwiegend neusynthetisierte D-RNS und R-RNS-Formen alkyliert. Die Methylierung aller RNS-Arten, vor allem der neusynthetisierten, beruht zum überwiegenden Anteil auf der Bildung von 7-Methylguanin. Die Inkorporation über den C1-pool spielt nur eine untergeordnete Rolle.
Die Guanin-Methylierung der m-RNS führt zur Desaggregation der Polysomen und ist sicher Grundlage der cytotoxischen Wirkung der Nitrosamine. Die Frage, ob eine kausale Beziehung zur carcinogenen Wirksamkeit besteht, wird diskutiert.
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Hennig, W., Kunz, W., Petersen, K. et al. Charakterisierung der durch Dimethylnitrosamin in vivo alkylierten RNS-Fraktionen der Leber. Z. Krebsforsch. 76, 167–180 (1971). https://doi.org/10.1007/BF00303562
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DOI: https://doi.org/10.1007/BF00303562