BIOCHEMICAL-MECHANISM OF TUMORIGENESIS IN MOUSE SKIN .9. INTERRELATION BETWEEN TUMOR-INITIATION BY 7,12-DIMETHYLBENZ[A]ANTHRACENE AND THE ACTIVITIES OF EPIDERMAL ARYLHYDROCARBON MONO-OXYGENASE AND EPOXIDE HYDRATASE

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. 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. 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. 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. 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. 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. 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. © 1979 Springer-Verlag.