title: Two 14-epi analogues of 1,25-dihydroxyvitamin D3 protect human keratinocytes against the effects of UVB.
abstract: In search of photoprotective agents, we recently demonstrated a protective effect of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] against different events mediated by ultraviolet B (UVB) in human keratinocytes. Pharmacological doses of 1,25(OH)(2)D(3) were required to obtain significant UVB protection; however, these doses cannot be used in vivo due to the calcemic properties of 1,25(OH)(2)D(3). Therefore, we evaluated the photoprotective capacities of two low-calcemic 14-epi analogues of 1,25(OH)(2)D(3), 19-nor-14-epi-23-yne-1,25(OH)(2)D(3) (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3) (TX 527). Using cultured human keratinocytes, we investigated the influence of TX 522 and TX 527 on two hallmark events in UVB-irradiated keratinocytes: the induction of apoptosis and the production of interleukin-6 (IL-6). Treatment of the keratinocytes with TX 522 or TX 527, 24 h before irradiation, resulted in a significant and dose-dependent reduction of both UVB-induced apoptosis and IL-6 production. Both analogues were equally efficient in their anti-UVB effects and at least 100 times more potent than 1,25(OH)(2)D(3). We further demonstrated that metallothionein (MT) mRNA expression was clearly induced by 1,25(OH)(2)D(3) and both analogues. MT acts as a radical scavenger in oxygen-mediated UVB injury and its induction may therefore be relevant for the anti-UVB effects of 1,25(OH)(2)D(3) and both analogues. Taken together, these findings create new perspectives for the use of active vitamin D analogues as photoprotective agents.
authors.affiliation: Laboratory for Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Gasthuisberg O&N9, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: De Haes
authors.forename: Marjan
authors.initials: M
authors.lastname: Garmyn
authors.forename: Annemieke
authors.initials: A
authors.lastname: Verstuyf
authors.forename: Pierre
authors.initials: P
authors.lastname: De Clercq
authors.forename: Maurits
authors.initials: M
authors.lastname: Vandewalle
authors.forename: Katleen
authors.initials: K
authors.lastname: Vantieghem
authors.forename: Hugo
authors.initials: H
authors.lastname: Degreef
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
authors.forename: Siegfried
authors.initials: S
authors.lastname: Segaert
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015850:Interleukin-6 / Q000096:biosynthesis; D015603:Keratinocytes / Q000528:radiation effects*; D008668:Metallothionein / Q000096:biosynthesis; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D014466:Ultraviolet Rays
chemical_list: D015850:Interleukin-6; D011837:Radiation-Protective Agents; D008668:Metallothionein; D002117:Calcitriol