Evidence for Involvement of Nonclassical Pathways in the Protection From UV‐Induced DNA Damage by Vitamin D–Related Compounds

Abstract

The vitamin D hormone, 1,25dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), and related compounds derived from vitamin D 3 or lumisterol as a result of metabolism via the enzyme CYP11A1, have been shown, when applied 24 hours before or immediately after UV irradiation, to protect human skin cells and skin from DNA damage due to UV exposure, by reducing both cyclobutane pyrimidine dimers (CPD) and oxidative damage in the form of 8-oxo-7,8-dihydro-2 0 -deoxyguanosine (8-OHdG). We now report that knockdown of either the vitamin D receptor or the endoplasmic reticulum protein ERp57 by small, interfering RNA (siRNA) abolished the reductions in UVinduced DNA damage with 20-hydroxyvitamin D 3 or 24-hydroxylumisterol 3, as previously shown for 1,25(OH) 2 D 3 . Treatment with 1,25(OH) 2 D 3 reduced oxygen consumption rates in UV-exposed and sham-exposed human keratinocytes and reduced phosphorylation of cyclic AMP response binding element protein (CREB). Both these actions have been shown to inhibit skin carcinogenesis after chronic UV exposure, consistent with the anticarcinogenic activity of 1,25(OH) 2 D 3 . The requirement for a vitamin D receptor for the photoprotective actions of 1,25(OH) 2 D 3 and of naturally occurring CYP11A1-derived vitamin D-related compounds may explain why mice lacking the vitamin D receptor in skin are more susceptible to UV-induced skin cancers, whereas mice lacking the 1αhydroxylase and thus unable to make 1,25(OH) 2 D 3 are not more susceptible.

Vitamin D Signaling in Psoriasis: Pathogenesis and Therapy

“…Other CYP11A1 vitamin D derivatives show similar anti-proliferative and pro-differentiation properties [ 88 , 93 , 102 , 132 , 133 , 134 , 135 ]. Similarly, vitamin D derivatives (resulted from CYP11A1 activity) protect from UV-induced DNA damages by the activation of Nrf2 and p53 defense mechanisms [ 73 , 77 , 134 , 136 ] and have shown anti-tumor activity against epidermal cancers [ 75 , 137 ]. Vitamin D derivatives have also shown antiproliferative activity on melanocytes [ 138 , 139 ] and fibroblasts with anti-fibrogenic actions [ 140 , 141 , 142 , 143 ], being dependent on RORγ [ 144 ].…”

An Appraisal to Address Health Consequences of Vitamin D Deficiency With Food Fortification and Supplements: Time to Act!

“…Vitamin D 3 that is produced in the skin and vitamin D 2 and vitamin D 3 , which are absorbed in the small intestine after being provided by the diet, are transferred to the blood where they are bound to the vitamin D binding protein (23)(24)(25)(26)(27)(28).…”

“…According to the classic concept, vitamin D (D representing both D 2 and D 3 ) has to be metabolized to 25(OH)D by cytochrome P 450 (CYP) enzymes CYP2R1 and CYP27A1 in the liver (23)(24)(25)(26)(27)(28). Transferred to the blood, 25(OH)D is then transported to a broad variety of different cell types, that include the skin, kidney, and various immune cells such as activated macrophages where it is transformed by CYP27B1 into its canonical biological active form 1,25dihydroxyvitamin D [1,25(OH) 2 D] (23-28).…”

“…Transferred to the blood, 25(OH)D is then transported to a broad variety of different cell types, that include the skin, kidney, and various immune cells such as activated macrophages where it is transformed by CYP27B1 into its canonical biological active form 1,25dihydroxyvitamin D [1,25(OH) 2 D] (23-28). The classical biological functions of 1,25(OH) 2 D are mediated via binding to the vitamin D receptor (VDR), which exerts its effects as an agonist-activated transcription factor that binds to VDR responsive elements (VDRE) in target genes, thereby regulating their expression (23)(24)(25)(26)(27)(28). Notably, recent scientific data convincingly show new emerging biological functions of non-canonical pathways of vitamin D metabolites that are induced by the action of CYP11A1, which has been characterized as a rate-limiting enzyme of steroidogenesis (23)(24)(25)(26)(27)(28).…”

“…The classical biological functions of 1,25(OH) 2 D are mediated via binding to the vitamin D receptor (VDR), which exerts its effects as an agonist-activated transcription factor that binds to VDR responsive elements (VDRE) in target genes, thereby regulating their expression (23)(24)(25)(26)(27)(28). Notably, recent scientific data convincingly show new emerging biological functions of non-canonical pathways of vitamin D metabolites that are induced by the action of CYP11A1, which has been characterized as a rate-limiting enzyme of steroidogenesis (23)(24)(25)(26)(27)(28). The first steps of these new non-canonical pathways of vitamin D metabolites are then followed by a broad variety of modifications involving other CYP enzymes, that include CYP27B1: D 3 ?…”