RT Journal Article
SR Electronic
T1 Production of 22-hydroxy-metabolites of vitamin D3 by cytochrome P450scc (CYP11A1) and analysis of their biological activities on skin cells.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.111.040071
DO 10.1124/dmd.111.040071
A1 Robert C Tuckey
A1 Wei Li
A1 Haleem Z Shehabi
A1 Zorica Janjetovic
A1 Minh N Nguyen
A1 Tae-Kang Kim
A1 Jianjun Chen
A1 Danielle E Howell
A1 Heather A E Benson
A1 Trevor Sweatman
A1 Donna M Baldisseri
A1 Andrzej Slominski
YR 2011
UL http://dmd.aspetjournals.org/content/early/2011/06/15/dmd.111.040071.abstract
AB Cytochrome P450scc (CYP11A1) can hydroxylate vitamin D3 producing 20S-hydroxyvitamin D3 [20(OH)D3] and 20S,23-dihydroxyvitamin D3 [20,23(OH)2D3] as the major metabolites. These are biologically active acting as partial vitamin D receptor [VDR] agonists. Minor products include 17-hydroxyvitamin D3, 17,20-dihydroxyvitamin D3 and 17,20,23-trihydroxyvitamin D3. In the current study we have further analyzed the reaction products from P450scc action on vitamin D3 and have identified two 22-hydroxy-derivatives as products, 22-hydroxyvitamin D3 [22(OH)D3] and 20S,22-dihydroxyvitamin D3 [20,22(OH)2D3]. The structures of both of these derivatives were determined by NMR. P450scc could convert purified 22(OH)D3 to 20,22(OH)2D3. The 20,22(OH)2D3 could also be produced from 20(OH)D3 and was metabolized to a trihydroxyvitamin D3 product. We compared the biological activities of these new derivatives to those of 20(OH)D3, 20,23(OH)2D3 and 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. 1,25(OH)2D3, 20(OH)D3, 22(OH)D3, 20,23(OH)2D3 and 20,22(OH)2D3 significantly inhibited keratinocyte proliferation in a dose dependent manner. The strongest inducers of involucrin expression (a marker of keratinocyte differentiation) were 20,23(OH)2D3, 20,22(OH)2D3, 20(OH)D3 and 1,25(OH)2D3, with 22(OH)D3 having a heterogeneous effect. Little or no stimulation of CYP24 mRNA expression was observed for all the analogues tested except for 1,25(OH)2D3. All the compounds stimulated VDR translocation from the cytoplasm to the nucleus with 22(OH)D3 and 20,22(OH)2D3 having less effect than 1,25(OH)2D3 and 20(OH)D3. Thus we have identified 22(OH)D3 and 20,22(OH)2D3 as products of CYP11A1 action on vitamin D3 and shown that like 20(OH)D3 and 20,23(OH)2D3, they are active on keratinocytes via the VDR, however, showing a degree of phenotypic heterogeneity in comparison to other P450scc-derived hydroxy-metabolites of vitamin D3.