title: Systemic administration of the apocarotenoid bixin protects skin against solar UV-induced damage through activation of NRF2.
abstract: Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis, and an urgent need exists for improved molecular photoprotective strategies different from (or synergistic with) photon absorption. Recent studies suggest a photoprotective role of cutaneous gene expression orchestrated by the transcription factor NRF2 (nuclear factor-E2-related factor 2). Here we have explored the molecular mechanism underlying carotenoid-based systemic skin photoprotection in SKH-1 mice and provide genetic evidence that photoprotection achieved by the FDA-approved apocarotenoid and food additive bixin depends on NRF2 activation. Bixin activates NRF2 through the critical Cys-151 sensor residue in KEAP1, orchestrating a broad cytoprotective response in cultured human keratinocytes as revealed by antioxidant gene expression array analysis. Following dose optimization studies for cutaneous NRF2 activation by systemic administration of bixin, feasibility of bixin-based suppression of acute cutaneous photodamage from solar UV exposure was investigated in Nrf2(+/+) versus Nrf2(-/-) SKH-1 mice. Systemic administration of bixin suppressed skin photodamage, attenuating epidermal oxidative DNA damage and inflammatory responses in Nrf2(+/+) but not in Nrf2(-/-) mice, confirming the NRF2-dependence of bixin-based cytoprotection. Taken together, these data demonstrate feasibility of achieving NRF2-dependent cutaneous photoprotection by systemic administration of the apocarotenoid bixin, a natural food additive consumed worldwide.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy & Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Shasha
authors.initials: S
authors.lastname: Tao
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy & Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Sophia L
authors.initials: SL
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy & Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rojo de la Vega
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy & Arizona Cancer Center, University of Arizona, Tucson, AZ, USA. Electronic address: dzhang@pharmacy.arizona.edu.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy & Arizona Cancer Center, University of Arizona, Tucson, AZ, USA. Electronic address: wondrak@pharmacy.arizona.edu.
authors.forename: Georg T
authors.initials: GT
authors.lastname: Wondrak
mesh_terms: D000818:Animals; D002338:Carotenoids / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D015603:Keratinocytes / Q000187:drug effects* / Q000528:radiation effects; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects* / Q000528:radiation effects; D013472:Sunlight / Q000009:adverse effects; D014162:Transfection; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D051267:NF-E2-Related Factor 2; D002338:Carotenoids; C004588:bixin
keywords: Antioxidant gene expression; Bixin; NRF2; Skin photodamage; Systemic photoprotection