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.

High‐energy visible light at ambient doses and intensities induces oxidative stress of skin—Protective effects of the antioxidant and Nrf2 inducer Licochalcone A in vitro and in vivo

“…Our investigations provide evidence for VIS‐protective effects of a specific, well‐defined LicA‐containing plant extract at much lower concentration (0.025%). Other plant‐derived antioxidants like tanshinone (5 µmol/L), quercetin (7.5 µmol/L), caffeic acid (15 µmol/L), salidroside (20 µmol/L), bixin (20 µmol/L), and the MAAs shinorine and porphyra‐334 (100 µmol/L) also induce Nrf2, however, at higher concentrations than LicA (1µmol/L). This highlights the importance of Nrf2 activation for the reduction of VIS‐induced oxidative stress.…”

“…Recent evidence suggests that plant‐derived antioxidants can protect VIS‐exposed skin from ROS‐induced oxidative stress, but their effects on Nrf2 remain to be established. A number of botanical ingredients including bixin, salidroside, tanshinones, caffeic acid, ferulic acid, quercetin, rutin, and the algae‐derived mycosporine‐like amino acids (MAAs) shinorine and porphyra‐334 were shown to mitigate UV‐induced cell damage via upregulation of Nrf2, but little is known about their protective effects against VIS. Licochalcone A (LicA) extracted from the roots of Glycyrrhiza inflata was identified as very potent antioxidant, inhibiting of UV‐induced ROS generation, and activator of Nrf2 in primary human fibroblasts .…”

Norbixin Protects Retinal Pigmented Epithelium Cells and Photoreceptors against A2E-Mediated Phototoxicity In Vitro and In Vivo

“…norbixin proved at least as efficient as PBN (Fig 7). Similarly, an efficient protection of the skin against UV was observed 48 hours after a single intraperitoneal injection of bixin (200 mg/kg) in rats [77]. …”

“…There is indeed good evidence that Nrf2 is involved in the protection of RPE against degeneration [89]. Nfr2 activation was described for lutein [90,91], zeaxanthin [92], astaxanthin [93] and bixin [77], but these effects were not always observed with RPE cells, so they may require confirmation using appropriate target cells.…”

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials

“…A team from the Arizona Cancer Center has recently reported that intra-peritoneal injection of bixin activates the transcription factor Nrf2 and thereby induces an antioxidant response in a mouse model of UV-induced photodamage and inflammation. Bixin-treated animals had significantly decreased UV-induced oxidative DNA damage and inflammation compared to control animals 138 . However, one potential issue is the relatively high daily dose used (equivalent to 16 mg/kg in humans or 1,200 mg for a 160 pound human 139 ), which is 33% higher than acceptable daily intake (ADI) recommended by the World Health Organization 138 .…”