The goal of this project is to determine the role of the aryl hydrocarbon hydroxylase (AHH) system in mouse skin tumorigenesis by methylated and non-methylated polycyclic hydrocarbons. Pursuant to this goal, we will examine the effects of some tumorigenic modifying agents on 7,12-dimethylbenz(a)anthracene (DMBA), 3-methylcholanthrene (MC), benzo(a)pyrene (BP) and 1,2,5,6-dibenzanthracene (DBA) mouse skin tumorigenesis and metabolism. We shall determine the effects of 7,8-benzoflavone, 5,6-benzoflavone, phenobarbital, butylated hydorxytoluene, and fluocinolone acetonide when administered to mice either topically or in the diet on the initiation of skin tumors by topical treatment of DMBA, MC, BP and DBA. An examination of the effects of the above tumorigenic modifying agents applied in vivo or added in vitro on the mouse epidermal microsomal AHH activity will be conducted. The conversion of radioactive DMBA, MC, BP and DBA to organic solvent-soluble metabolites separated by high-pressure liquid chromatography will be used as the overall assessment of the AHH activity. The effects of the modifying agents applied in vivo on the epoxidation and hydration reactions specifically will be determined as follows: (1) the NADpH-requiring, microsomal catalyzed in vitro covalent binding of radioactive DMBA, MC, BP and DBA to DNA in the presence of the potent epoxide hydrase inhibitor 1,1,1-trichloropropene 2,3-oxide will be determined (index of activation step?) and 2) the activity of the expoxide hydrase enzyme(s) will be assayed by the in vitro conversion of K-region epoxides of DMBA, MC, BP and DBA to dihydrodiols which will be measured by high-pressure liquid chromatography analysis (index of detoxification step?). The results of this project should give us a better understanding of polycyclic hydrocarbon carcinogenesis and possible a rational approach to the chemoprophylaxis of environmental carcinogens.