Epidermal Pyridoxal 5′-Phosphate Depletion, Inhibition of DNA Synthesis, and Inhibition of the Expression of Ornithine Decarboxylase Activity by the Vitamin B-6 Antagonist 4′-Deoxypyridoxine

Abstract

The induction of ornithine decarboxylase (ODC) activity may be an essential component of skin tumor promotion. ODC requires pyridoxal 5'-phosphate (PLP) as a cofactor. We have measured the epidermal PLP concentration and investigated its relationship to DNA synthesis and ODC activity in the hairless mouse. The epidermal PLP concentration was approximately 1.0 microgram/g. When tape-stripping was used to induce ODC activity in the epidermis the concentration of PLP was significantly elevated 4.5 h later at the time of peak ODC activity and when DNA synthesis was reduced. Systemic treatment with the vitamin B-6 antagonist 4'-deoxypyridoxine (4-DOP) significantly reduced the epidermal PLP concentration and DNA synthesis. The ODC activity induced in the epidermis 4.5 after tape-stripping in 4-DOP-treated mice was only 17% of that induced in untreated tape-stripped controls. In in vitro experiments it was shown that while 4-DOP does not inhibit ODC activity, a major metabolite of 4-DOP-phosphate (Ki .06 mM), does. In mixing experiments it was shown that the epidermal extracts from 4-DOP-treated mice did not contain significant amounts of ODC inhibitors. 4-DOP may inhibit ODC induction in the epidermis by depleting the PLP content.