Summary
The metabolism of the radioactively labeled tumor promoting phorbol esters (TPA and PDD) and of the inactive epimer of PDD (4α-PDD) were studied 12 h after topical application on the back skin of mice. The results obtained were compared with metabolic changes of the labeled phorbol derivatives after in vitro incubation with embryonic mouse skin and with cultures of HeLa and L-cells.
In mouse skin PDD and 4αPDD are poorly metabolized within 12 h as was shown previously for TPA.
In monolayer and suspension cultures of HeLa cells where at very low concentrations (10−8M) only phorbol esters with tumor promoting activity in mouse skin block DNA synthesis and stimulate choline incorporation into lipids, hardly any metabolic changes were observed in biologically active as well as in inactive phorbol derivatives. In monolayer and suspension cultures of L-cells all phorbol derivatives tested are metabolized to a considerable extent within 12 h, which correlates with the lack of response in blocking DNA synthesis and stimulation of lipid turnover.
From these results it is concluded that tumor promoting phorbol esters need no metabolic activation.
Zusammenfassung
Der Stoffwechsel der radioaktiv markierten und tumorpromovierenden Phorbolester TPA und PDD, sowie des zu PDD epimeren und inaktiven 4α-PDD, wurde 12 Std nach topischer Applikation auf die Rückenhaut von Mäusen untersucht. Die Ergebnisse werden mit dem Stoffwechsel von Phorbolderivaten nach in vitro Inkubation mit embryonaler Mäusehaut und mit Zellkulturen von HeLa-sowie L-Zellen verglichen.
Wie bereits früher im Falle von TPA festgestellt, werden in der Mäusehaut auch PDD und 4α-PDD innerhalb von 12 Std kaum metabolisch verändert.
In Monolayer-und Suspensions-Kulturen von HeLa-Zellen, wo nur die tumor-promovierenden Phorbolderivate bereits in sehr niedrigen Konzentrationen (10−8M) die DNA-Synthese blockieren und den Einbau von Cholin in Phospholipide stimulieren, wurden nur geringe metabolische Veränderungen der getesteten Phorbolderivate beobachtet. Nach Inkubation mit Monolayer-und Suspensionskulturen von l-Zellen, die diese Beeinflussung des DNA-und Lipidstoffwechsels durch Phorbolderivate nicht zeigen, werden dagegen alle hier untersuchten Phorbolderivate innerhalb von 12 Std in erheblichem Ausmaß metabolisiert.
Die erhobenen Befunde sprechen gegen eine metabolische Aktivierung von Phorbolestern.
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IVth Communication: Z. Krebsforschung 76, 113–123 (1971)
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Kreibich, G., Süss, R. & Kinzel, V. On the biochemical mechanism of tumorigenesis in mouse skin. V. studies of the metabolism of tumor promoting and non promoting phorbol derivatives in vivo and in vitro . Z. Krebsforsch. 81, 135–149 (1974). https://doi.org/10.1007/BF00304153
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DOI: https://doi.org/10.1007/BF00304153