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  • Title: Metabolism of 1alpha-hydroxyvitamin D3 by cytochrome P450scc to biologically active 1alpha,20-dihydroxyvitamin D3.
    Author: Tuckey RC, Janjetovic Z, Li W, Nguyen MN, Zmijewski MA, Zjawiony J, Slominski A.
    Journal: J Steroid Biochem Mol Biol; 2008 Dec; 112(4-5):213-9. PubMed ID: 19000766.
    Abstract:
    Cytochrome P450scc (CYP11A1) metabolizes vitamin D3 to 20-hydroxyvitamin D3 as the major product, with subsequent production of dihydroxy and trihydroxy derivatives. The aim of this study was to determine whether cytochrome P450scc could metabolize 1alpha-hydroxyvitamin D3 and whether products were biologically active. The major product of 1alpha-hydroxyvitamin D3 metabolism by P450scc was identified by mass spectrometry and NMR as 1alpha,20-dihydroxyvitamin D3. Mass spectrometry of minor metabolites revealed the production of another dihydroxyvitamin D3 derivative, two trihydroxy-metabolites made via 1alpha,20-dihydroxyvitamin D3 and a tetrahydroxyvitamin D3 derivative. The Km for 1alpha-hydroxyvitamin D3 determined for P450scc incorporated into phospholipid vesicles was 1.4 mol substrate/mol phospholipid, half that observed for vitamin D3. The kcat was 3.0 mol/min/mol P450scc, 6-fold lower than that for vitamin D3. 1alpha,20-Dihydroxyvitamin D3 inhibited DNA synthesis by human epidermal HaCaT keratinocytes propagated in culture, in a time- and dose-dependent fashion, with a potency similar to that of 1alpha,25-dihydroxyvitamin D3. 1alpha,20-Dihydroxyvitamin D3 (10 microM) enhanced CYP24 mRNA levels in HaCaT keratinocytes but the potency was much lower than that reported for 1alpha,25-dihydroxyvitamin D3. We conclude that the presence of the 1-hydroxyl group in vitamin D3 does not alter the major site of hydroxylation by P450scc which, as for vitamin D3, is at C20. The major product, 1alpha,20-dihydroxyvitamin D3, displays biological activity on keratinocytes and therefore might be useful pharmacologically.
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