Ultraviolet A sensitivity in Smith–Lemli–Opitz syndrome: Possible involvement of cholesta-5,7,9(11)-trien-3β-ol

Chignell, Colin F.; Kukielczak, Barbara M.; Sik, Robert H.; Bilski, Piotr; He, Yu‐Ying

doi:10.1016/j.freeradbiomed.2006.04.021

Cited by 30 publications

(34 citation statements)

References 29 publications

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“…Thus, observed UVB-driven formation of triene derivatives for several 5,7-dienes such as 7DHC or 17,20-diOH derivatives of 7DHP [19] is a common reaction with potential implications for photosensitivity of the skin [9]. …”

Section: Discussionmentioning

confidence: 99%

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Synthesis and photochemical transformation of 3β,21-dihydroxypregna-5,7-dien-20-one to novel secosteroids that show anti-melanoma activity

Żmijewski

Chen

et al. 2011

Steroids

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We have synthesized 3β,21-dihydroxypregna-5,7-dien-20-one (21(OH) 7DHP) and used UVB radiation to induce its photoconversion to analogues of vitamin D (pD), lumisterol (pL) and tachysterol (pT). The number and character of the products and the dynamics of the process were dependent on the UVB dose. The main products: pD and pT compounds were characterized by UV absorption, MS and NMR spectroscopy after RP-HPLC chromatography. In addition, formation of multiple oxidized derivatives of the primary products was detected and one of these derivatives was characterized as oxidized 21-hydroxyisotachysterol compound (21(OH)oxy-piT). These newly synthesized compounds inhibited growth of human melanoma cells in a dose dependent manner, with greater or equal potency to calcitriol. 3β,21-Dihydroxy-9β,10α-pregna-5,7-dien-20-one (21(OH)pL) and 21(OH)oxy-piT had higher potency against pigmented melanoma cells, while the EC 50 for compounds 21(OH)7DHP and (5Z,7E)-3β,21-dihydroxy-9,10-secopregna-5,7,10(19)-trien-20-one (21(OH)pD) were similar in both pigmented and nonpigmented cells. Moreover, 21(OH)7DHP and its derivatives inhibited proliferation of human epidermal HaCaT keratinocytes, albeit at a lower activity compared to melanoma cells. Importantly, 21(OH)7DHP derivatives strongly inhibited the colony formation of human melanoma cells with 21(OH)pD being the most potent. The potential mechanism of action of newly synthesized compounds was similar to that mediated by 1,25(OH) 2 D 3 and involved ligandinduced translocation of vitamin D receptor into the nucleus. In summary, we have characterized for the first time products of UVB-induced conversion of 21(OH)7DHP and documented that these compounds have selective, inhibitory effects on melanoma cells.

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Section: Discussionmentioning

confidence: 99%

“…Similar to 7DHC, such compounds [9, 10, 13, 17–19], are sensitive to UVB-induced photoconversion to vitamin D, lumisterol and tachysterol analogues [17–19]. Recently, it was shown that cytochrome P450scc is capable of the oxidation and cleavage of the side chain of 7-DHC to produce 7-dehydropregnenolone (7DHP) [17, 20].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and photochemical transformation of 3β,21-dihydroxypregna-5,7-dien-20-one to novel secosteroids that show anti-melanoma activity

Żmijewski

Chen

et al. 2011

Steroids

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“…The ROS are then responsible for the observed rapid increase in [Ca 2+ ] i and synthesis of PGE 2 . Further reactions of the primary radical also leads to formation of a cholesterol triene that has recently been suggested as a chromophore for the photosensitivity in SLOS [61]. Continued chain reaction oxidation of membrane unsaturated lipids also provides a mechanism for production of ROS (>120 min, Fig.…”

Section: Discussionmentioning

confidence: 99%

7-Dehydrocholesterol enhances ultraviolet A-induced oxidative stress in keratinocytes: Roles of NADPH oxidase, mitochondria, and lipid rafts

Valencia

Rajadurai

Carle

et al. 2006

Free Radical Biology and Medicine

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Long wavelength solar UVA radiation stimulates formation of reactive oxygen species (ROS) and prostaglandin E 2 (PGE 2 ), which are involved in skin photosensitivity and tumor promotion. High levels of 7-dehydrocholesterol (7-DHC), the precursor to cholesterol, cause exaggerated photosensitivity to UVA in patients with Smith-Lemli-Opitz syndrome (SLOS). Partially replacing cholesterol with 7-DHC in keratinocytes rapidly (<5 min) increased UVA-induced ROS, intracellular calcium, phospholipase A 2 activity, PGE 2 , and NADPH oxidase activity. UVA-induced ROS and PGE 2 production were inhibited in these cells by depleting the Nox1 subunit of NADPH oxidase using siRNA or using a mitochondrial radical quencher, MitoQ. Partial replacement of cholesterol with 7-DHC also disrupted membrane lipid raft domains, although depletion of cholesterol, which also disrupts lipid rafts, did not affect UVA-induced increases in ROS and PGE 2 . Phospholipid liposomes containing 7-DHC were more rapidly oxidized by a free radical mechanism than those containing cholesterol. These results indicate that 7-DHC enhances rapid UVA-induced ROS and PGE 2 formation by enhancing free radical-mediated membrane lipid oxidation and suggests that this mechanism might underlie the UVA-photosensitivity in SLOS.

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“…Based on subsequent work by other groups, it is likely that 7DHC or 7DHC metabolites underlie the UVA sensitivity. Chignell et al ( 50 ) showed that the UVA photosensitivity in SLOS might be a result of oxidative stress induced by photolysis of cholesta-5,7,9(11)-trien-3 ␤ -ol or 9-DDHC, and Valencia et al ( 51 ) showed that 7DHC enhances UVA-induced reactive oxidative stress by enhancing free radical-mediated membrane lipid oxidation.…”

Section: Slos Phenotypementioning

confidence: 99%

Malformation syndromes caused by disorders of cholesterol synthesis

Porter

Herman

2011

Journal of Lipid Research

400

440

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Ultraviolet A sensitivity in Smith–Lemli–Opitz syndrome: Possible involvement of cholesta-5,7,9(11)-trien-3β-ol

Cited by 30 publications

References 29 publications

Synthesis and photochemical transformation of 3β,21-dihydroxypregna-5,7-dien-20-one to novel secosteroids that show anti-melanoma activity

Synthesis and photochemical transformation of 3β,21-dihydroxypregna-5,7-dien-20-one to novel secosteroids that show anti-melanoma activity

7-Dehydrocholesterol enhances ultraviolet A-induced oxidative stress in keratinocytes: Roles of NADPH oxidase, mitochondria, and lipid rafts

Malformation syndromes caused by disorders of cholesterol synthesis

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