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On the biochemical mechanism of tumorigenesis in mouse skin

IX. Interrelation between tumorinitiation by 7,12-dimethylbenz[a]anthracene and the activities of epidermal arylhydrocarbon monooxygenase and epoxide hydratase
  • W. G. Pyerin
  • E. Hecker
Original Papers Experimental Oncology

Summary

In the two stage model system of chemical carcinogenesis on mouse skin (initiator: subcarcinogenic dose of DMBA, promoter: TPA; both applied topically) we find:
  1. 1.

    Positive correlation of the dose of DMBA administered with both the extent of initation of tumors and the extent of induction of AHM in the target tissue (dorsal epidermis). No such correlation was found to exist for the specific activity of EH.

     
  2. 2.

    No change in the extent of initiation results when simultaneously with DMBA the cytochrome P-450 inducer PB or the cytochrome P-450 inhibitor SKF is administered.

     
  3. 3.

    A drastic depression of initiation is found when the cytochrome P-448 inhibitor BF is administered simultaneously with or within the first hours after DMBA. At≥7 h after administration of DMBA the inhibitor no longer interferes with initiation.

     
  4. 4.

    PB does not change specific activity of AHM whereas SKF as well as BF strongly inhibit AHM activity during the first hours after their application; in case of SKF AHM activity returns to nearly its normal level within about 20 h after administration, whereas in case of BF at times >20 h after administration an elevated level of AHM activity is observed.

     
  5. 5.

    The specific activity of EH apparently is not changed upon treatment of the target tissue with these drugs independent of whether or not they alter the extent of initiation. Thus, the process of initiation seems not to be controlled by changes in the specific activity of EH.

     
  6. 6.

    Comparison of the time-dependency of the inhibition of tumor initiation by BF and the increase of specific activity of AHM after application of DMBA reveals indirect evidence that the positive correlation of the dose of DMBA with both the extent of tumor initiation and the extent of induction of AHM is rather one by chance. Thus, the constitutive level of cytochrome P-448 dependent AHM activity present in epidermis at the time of initiation suffices for the generation of metabolites of DMBA which initiate or mediate initiation.

     

Key words

Tumorgenesis in Mouse Skin 7,12-Dimethylbenz[a]anthracene Arylhydrocarbon monooxygenase Epoxide hydratase Tumorinitiation 

Zum biochemischen Mechanismus der Tumorgenese der Mäusehaut

Zusammenfassung

Für das Zwei-Stufen-Modell der chemischen Carcinogenese an der Mäusehaut (Initiator: subcarcinogene Dosis an DMBA; Promotor: 12-0-Tetradecanoylphorbol-13-acetat (TPA); beide topisch verabreicht) ergibt sich:
  1. 1.

    Die applizierte Dosis an DMBA steht in positivem Zusammenhang sowohl mit dem Ausmaß der Tumorinitiation als auch mit dem der Induktion der AHM im zielgewebe (Epidermis der Rückenregion). Die spezifische Aktivität der EH zeigt eine solche Beziehung nicht.

     
  2. 2.

    Das Ausmaß der Initiation ändert sich nicht, wenn gleichzeitig mit DMBA der Cytochrom-P-450-Induktor PB oder der P-450-Inhibitor SKF appliziert wird.

     
  3. 3.

    Die Initiation wird drastisch vermindert, wenn gleichzeitig mit DMBA oder innerhalb der ersten Stunden nach DMBA-Gabe der Cytochrom-P-448-Inhibitor BF verabreicht wird. Wird der Inhibitor erst später, nämlich ≧7 Std nach DMBA-Gabe appliziert, ist eine Beeinflussung der Initiation praktisch nicht mehr zu beobachten.

     
  4. 4.

    Während die Applikation von PB zu keiner Änderung der spezifischen Aktivität der AHM führt, rufen sowohl SKF als auch BF ein starkes Absinken innerhalb der ersten Stunden hervor; die AHM-Aktivität erreicht im Falle von SKF nach etwa 20 Std nahezu wieder ihr Normalniveau, hingegen steigt sie im Falle von BF nach ≥20 Std deutlich darüber hinaus an.

     
  5. 5.

    Die spezifische Aktivität der EH scheint sich während der Initiationsphase nicht zu ändern unabhängig davon, ob eine Behandlung der Tiere mit den genannten Substanzen das Ausmaß der Initiation ändert oder nicht. Ein Eingriff in den Initiationsprozeß durch die EH über eine Änderung ihrer spezifischen Aktivität ist daher nicht anzunehmen.

     
  6. 6.

    Ein Vergleich der Zeitabhängigkeit des inhibierenden Effektes von BF auf die Tumorinitiation mit der der Zunahme der spezifischen Aktivität der AHM nach Verabreichen von DMBA macht indirekt deutlich, daß der positive Zusammenhang, der zwischen DMBA-Dosis, dem Ausmaß der Tumorinitiation und dem der AHM-Induktion besteht, eher zufällig ist. Daraus folgt, daß die konstitutive, zum Zeitpunkt der Initiation in der Epidermis vorhandene Aktivität an Cytochrom-P-448-abhängiger AHM genügt, um jene DMBA-Metaboliten zu generieren, die unmittelbar oder mittelbar zur Initiation führen.

     

Schlüsselwörter

Tumorgenese in der Mäusehaut 7,12-Dimethylbenz[a]-anthracen Arylkohlenwasserstoff-Monooxygenase Epoxid-Hydratase Tumorinitiation 

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Copyright information

© Springer-Verlag 1979

Authors and Affiliations

  • W. G. Pyerin
    • 1
  • E. Hecker
    • 1
  1. 1.Deutsches KrebsforschungszentrumHeidelbergFederal Republic of Germany

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