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12-O-Tetradecanoylphorbol-13-acetate-dependent Induction of Xanthine Dehydrogenase and Conversion to Xanthine Oxidase in Murine Epidermis¹

The University of Texas System Cancer Center, Science Park—Research Division, Smithville, Texas 78957

Both xanthine dehydrogenase (XD) and xanthine oxidase (XO) catalyze the conversion of hypoxanthine to xanthine, and xanthine to uric acid. Topical application of a promoting dose of 12-O-tetradecanoylphorbol-13-acetate (TPA) to the dorsal skin of female SENCAR mice resulted in a 3.0–3.5-fold elevation of epidermal XO specific activity. Epidermal XO specific activity was maximally elevated 48–96 h after TPA treatment, and required 11 days to return to control levels. Although TPA increased the XO/(XD + XO) ratio from 0.45 to 0.7, the conversion of preexisting XD to XO could not solely account for the TPA-dependent elevation in XO specific activity since control XD plus XO activity was less than just the XO activity in TPA-treated epidermis. Topical application of cycloheximide simultaneously with, or 12 h after, TPA treatment inhibited the TPA-dependent increases in the XO/(XD + XO) ratio and XO specific activities. Collectively, these results suggest that the increased XO activity detected following TPA treatment is the consequence of TPA-induced XD synthesis, and a conversion of existing and newly synthesized XD to XO. In addition, the in vivo promoting activities of analogues of TPA could be correlated with their abilities to elevate XO activity (TPA > phorbol-12,13-dibenzoate >> 4-O-methyl-TPA = phorbol).

¹ This project was supported by National Cancer Institute Grants CA-40823 and CA-34469, Department of Health and Human Services, and by American Cancer Institute Grant IFN-16.

² To whom requests for reprints should be addressed, at University of Texas System, Cancer Center, Science Park, Research Division, Smithville, TX 78957.

³ Postdoctoral fellow supported by National Institutes of Health training Grant CA-09480, Department of Health and Human Services.

Received 9/22/86. Revised 12/17/86. Accepted 12/30/86.

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