title: Inhibition of poly(adenosine diphosphate-ribose) polymerase by the active form of vitamin D.
abstract: Vitamin D is well characterized for its role in mineral homeostasis and maintenance of normal skeletal architecture. Vitamin D has been demonstrated to exert anti-inflammatory effects in a variety of disease states including diabetes, arthritis and inflammatory bowel disease. In these diseases poly[adenosine diphosphate (ADP)-ribose] polymerase (PARP) inhibitors have also proved effective as anti-inflammatory agents. Here we present data demonstrating that the active metabolite of vitamin D, 1alpha,25-dihydroxy-vitamin D3, is a PARP inhibitor. UV irradiation-mediated PARP activation in human keratinocytes can be inhibited by treatment with vitamin D, 7-dehydrocholesterol or 1alpha,25-dihydroxyvitamin D3. Inhibition of cytochrome P450 reversed the PARP inhibitory action of vitamin D and 7-dehydrocholesterol, indicating that conversion to 1alpha,25-dihydroxyvitamin D3 mediates their PARP inhibitory action. Vitamin D may protect keratinocytes against over-activation of PARP resulting from exposure to sunlight. PARP inhibition may contribute to the pharmacological and anti-inflammatory effects of vitamin D.
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton BN2 4GJ, UK. j.g.mabley@brighton.ac.uk
authors.forename: Jon G
authors.initials: JG
authors.lastname: Mabley
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wallace
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.forename: Kanneganti
authors.initials: K
authors.lastname: Murphy
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014807:Vitamin D; D011065:Poly(ADP-ribose) Polymerases; D002117:Calcitriol