Summary
Following the well established prevention of chemical carcinogenesis by vitamin A in several species of laboratory animals, we performed in vitro studies with human diploid fibroblasts in culture. Vitamin A-palmitate, alltransretinoic acid and the analogue compound Ro 10-9359 were found to reduce the formation of active intermediates following the administration of G3H Benzo(a)pyrene to the cells. This effect which lead to a considerable decrease of alkylated DNA is not based on a direct inhibition of Benzpyrene metabolizing enzymes by the retinoids but by a preferential inhibition of the de novo synthesis of these enzymes. This caused the well known substrate mediated enzyme induction of benzpyrene metabolizing enzymes to cease. From our data we conclude that the mechanism of the cancer protective effect of vitamin A with respect to certain carcinogens is based on an inhibited activation of procarcinogens. This effect can also be expected in human tissues.
Zusammenfassung
Ausgehend von bekannten tierexperimentellen Daten über eine protektive Wirkung von Vitamin A und seinen Analogen gegenüber der Tumor-Auslösung durch chemische Cancerogene wurden in vitro-Untersuchungen an Fibroblastenkulturen vom Menschen durchgeführt. Wir untersuchten den Einfluß von Vitamin A-Palmitat und seinen chemischen Analogen Ro 10-9359 und All-Trans-Retinsäure auf den Abbau von G-3H-Benzo(a)pyren zu wasserlöslichen Produkten und die Adduktion radioativer Intermediate an die DNS. Retinoide reduzierten konzentrationsabhängig den enzymatischen Abbau von Benzpyren und die Benzpyren-abhängige Alkylierung von DNS, dabei hemmten Retinoide den enzymatischen Abbau von Benzpyren nicht direkt, sondern die substratabhängige Induktion der abbauenden Enzyme über eine Reduktion der Proteinsynthese, die als 3H-Leucin-Einbau in Fibroblasten gemessen wurde. Anders als durch Cycloheximid und Actinomycin D kam es durch Retinoide nicht zur generellen Blockade der Eiweißsynthese, sondern zur bevorzugten Hemmung der induzierbaren Enzyme des Benzpyrenabbaus.
Wir schließen aus diesen Untersuchungen, daß der Mechanismus der protektiven Wirkung von Retinoiden gegenüber bestimmten chemischen Cancerogenen über eine Hemmung der Aktivierung von Pro-Cancerogenen führt, und daß diese protektive Wirkung auch an Zellen vom Menschen nachweisbar ist.
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Abbreviations
- BP :
-
Benzo(a)pyren
- FCS :
-
Fetales Kälberserum
- DNS :
-
Desoxyribonucleinsäure
- RNS :
-
Ribonucleinsäure
- ANF :
-
Alpha-Naphthoflavon
- CH :
-
Cycloheximid
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Kohl, F.V., Rüdiger, H.W. In vitro-Untersuchungen an menschlichen Zellkulturen zur Tumorprophylaxe durch Vitamin A. J Cancer Res Clin Oncol 93, 149–160 (1979). https://doi.org/10.1007/BF00406572
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DOI: https://doi.org/10.1007/BF00406572