Altered Patterns of Cutaneous Xenobiotic Metabolism in UVB-Induced Squamous Cell Carcinoma in SKH-1 Hairless Mice

Abstract

Cutaneous xenobiotic metabolizing enzymes including aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECD), epoxide hydrolase (EH) and glutathione S-transferase (GST) activities were examined in SKH hairless mice chronically irradiated with UVB to induce squamous cell carcinoma (SCC). Enzyme activities in irradiated tumor-bearing skin were compared to those present in the skin of nonirradiated control animals as well as in unirradiated non-tumor bearing skin sites of the SCC-bearing mice. The inducibility of skin AHH and ECD in each set of animals was assessed following a single topical application of coal tar (1 ml/100 g). Enzyme-mediated binding of [3H]benzo(a)pyrene (BP) and its metabolite 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE-I) to epidermal DNA was also evaluated. Basal AHH and ECD activities in microsomes from UVB-irradiated SCC-bearing dorsal skin were 4.6- and 4.8-fold lower than those in dorsal skin of nonirradiated control animals. Enzyme activities in non-tumor bearing ventral skin from the UVB-irradiated SCC-bearing mice also were 2.2 to 2.8-fold lower as compared to activities in the nonirradiated control animals. The reduction in AHH activity paralleled the levels of enzyme-mediated binding of radiolabeled BP metabolites and of BPDE-I to epidermal DNA. GST activity was found to be increased (173%) in non-tumor bearing ventral skin of UVB-irradiated mice whereas no difference in activity between SCC-bearing dorsal skin and dorsal skin of control animals could be detected. EH activity was unchanged in each group of animals. Treatment with topically applied coal tar resulted in higher inducibility of AHH and ECD in both SCC-bearing (13-fold) as well as in non-tumor skin sites (6-fold) of UVB-irradiated mice than in skin of control animals (3-fold). Coal tar application also increased the covalent binding of [3H]BP and of the metabolite BPDE-I to skin DNA. This was greater in SCC-bearing dorsal skin (119-129%) than in nonirradiated skin of control animals (48-62%). Our studies suggest that the metabolism of BP by cutaneous cytochrome P-450 dependent monooxygenases is impaired in skin of mice irradiated chronically with UVB. The higher inducibility of these monooxygenases by topically applied coal tar and the enhancement of the associated enzyme-mediated covalent binding of BP metabolites and BPDE-I to epidermal DNA indicate that repetitive exposure of mammalian skin to UVB radiation can profoundly alter the activity and the inducibility of drug and carcinogen metabolizing enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)