Additive effects of ultraviolet B and crude coal tar on cutaneous carcinogen metabolism: possible relevance to the tumorigenicity of the Goeckerman regimen.
The effect of cutaneous exposure to ultraviolet B (UVB) radiation alone, to crude coal tar (CCT) alone, and to the combination of UVB and CCT on the inducibility of the microsomal cytochrome P-450-dependent carcinogen-metabolizing enzyme aryl hydrocarbon hydroxylase (AHH) and other monooxygenases such as 7-ethoxyresorufin O-deethylase (ERD) and 7-ethoxycoumarin O-deethylase (ECD) activities in the skin of neonatal rats was studied. Exposure of the animals to UVB (400-1600 mJ/cm2) alone resulted in a dose-dependent increase in cutaneous enzyme activities. At a UVB dose of 1200 mJ/cm2 increases in AHH, ECD, and ERD were 194%, 115%, and 244%, respectively. A single topical application of CCT (10 ml/kg) 24 h before sacrifice resulted in significant induction of AHH (350%), ECD (921%), and ERD (796%) activities. Treatment of animals with the same dose of CCT followed by UVB exposure resulted in additive and/or synergistic effects on AHH (858%), ECD (1229%), and ERD (1166%) activities in the skin. In contrast, exposure of animals to UVB prior to CCT application had effects no different from those of CCT alone. Epoxide hydrolase and glutathione S-transferase activities in skin from all experimental groups were not different from those of controls. High-pressure liquid chromatographic analysis of the metabolism of benzo[a]pyrene (BP) by cutaneous microsomes prepared from animals treated with UVB alone, CCT alone, and the combination of UVB and CCT revealed increased formation of all the metabolites in each experimental group. The largest increase in metabolite formation occurred in animals receiving CCT followed by UVB exposure. The inducibility of trans-7,8-diol formation by UVB alone and CCT alone was 203% and 435%, respectively, whereas with CCT followed by UVB it was 1065%. The differential responses in AHH activity were found to parallel the capacity of skin microsomal enzymes to enhance the binding of [3H]-BP to DNA. These studies indicate that the sequence of exposure to the components of the Goeckerman regimen in rodents greatly influences metabolic activity in skin. When applied in the same sequence employed in the Goeckerman regimen (CCT followed by UVB exposure) the additive effect upon catalytic activity essential for cancer initiation suggests a possible mechanism for the enhancement of human skin cancer in individuals exposed to this therapeutic regimen.
D000818:Animals; D003033:Coal Tar / Q000009:adverse effects*; D004851:Epoxide Hydrolases / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D012867:Skin / Q000201:enzymology / Q000648:ultrastructure; D012878:Skin Neoplasms / Q000209:etiology* / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
D003033:Coal Tar; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases