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1,25-Dihydroxyvitamin D₃ Regulates Estrogen Metabolism in Cultured Keratinocytes¹

Department of Medicine, Queen Elizabeth Hospital, University of Birmingham, Birmingham, United Kingdom B15 2TH; and the Department of Dermatology, Selly Oak Hospital (H.M.L.), Birmingham, United Kingdom B29 6JD

Address all correspondence and requests for reprints to: Dr. M. Hewison, Department of Medicine, Queen Elizabeth Hospital, University of Birmingham, Birmingham, United Kingdom B15 2TH. E-mail: M.Hewison{at}bham.ac.uk

Local estrogen metabolism may play an important role in modulating cell development in peripheral tissues such as breast, adipose, and bone. C₁₉ androgens are converted to C₁₈ estrogens by the enzyme aromatase, overexpression of which is associated with breast cancer. Interconversion of active estradiol (E₂) to inactive estrone is controlled by various isoforms of the enzyme 17ß-hydroxysteroid dehydrogenase (17ßHSD). We have studied the expression of these two enzymes in human keratinocytes and report rapid changes in 17ßHSD activity in response to treatment with 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃]. Keratinocytes cultured in serum-free medium showed aromatase activity of 2.5 fmol/h·mg cell protein, which was unaffected by any culture treatment. A much higher level of 17ßHSD activity was observed in the keratinocytes, predominantly conversion of E₂ to estrone (120 pmol/h·mg cell protein). This inactivation of E₂ increased in a dose-dependent fashion after treatment of the cells with antiproliferative doses of 1,25-(OH)₂D₃ (0.1–200 nM). The effect of 1,25-(OH)₂D₃ on 17ßHSD activity was enhanced by simultaneous treatment with dexamethasone, which also increased the antiproliferative action of 1,25-(OH)₂D₃. Reverse transcription-PCR and Northern analysis showed that keratinocytes expressed messenger RNA for three 17ßHSD isoenzymes (types I, II, and IV). Treatment with 1,25-(OH)₂D₃ (10 nM for 20 h) resulted in the up-regulation of messenger RNA levels for type 2 17ßHSD. Further RNA studies combined with E₂ binding experiments demonstrated the presence of estrogen receptors in the cultured keratinocytes. These data indicate that keratinocytes are potential targets for systemically or locally produced estrogens, which may, in turn, play a key role in the development of normal skin. In particular, we propose that 17ßHSD isoenzymes are key target genes for 1,25-(OH)₂D₃ in keratinocytes and may be an important feature of the antipsoriatic effects of vitamin D and its analogs.

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