Ultraviolet A sensitivity in Smith–Lemli–Opitz syndrome: Possible involvement of cholesta-5,7,9(11)-trien-3β-ol
Abstract
Smith-Lemli-Opitz syndrome (SLOS) is a severe developmental disorder caused by mutations in the DHCR7 gene coding for 7-dehydrocholesterol (7-DHC) reductase, the enzyme involved in the last step of cholesterol biosynthesis. SLOS homozygotes exhibit marked deficiency of cholesterol in plasma and tissues with concomitant increase in 7-DHC. Ultraviolet A (UVA) photosensitivity has been recognized as part of SLOS with maximal response occurring at 350 nm. 7-DHC itself has no UVA absorption and so cannot be the direct cause of SLOS photosensitivity. However, cholesta-5,7,9(11)-trien-3beta-ol (9-DDHC), a metabolite of 7-DHC, has been detected in plasma from SLOS patients. Because 9-DDHC has strong absorption in the UVA range (approximately 15,000 @ 324 nm), we have examined its photobiology to determine whether it could be involved in SLOS photosensitivity. High levels of 7-DHC (0.65 mg/100 g wet weight) and measurable amounts of 9-DDHC (0.042 mg/100 g wet weight) were found in skin lipids extracted from CD-1 mice treated with AY9944 (trans-1,4-bis(2-chlorobenzylaminomethyl)cyclohexane dihydrochloride), an inhibitor of 7-DHC reductase. Human HaCaT keratinocytes treated with 9-DDHC (10 microM) and then immediately exposed to UVA (15 J/cm2) exhibited an 88% decrease in viability (compared to dark controls). No damage was observed in cells exposed to 7-DHC/UVA or UVA alone. However, HaCaT keratinocytes treated with 7-DHC (5 microM) for 15 h and then exposed to UVA (30 J/cm2) were damaged. 9-DDHC was detected in keratinocytes incubated with 7-DHC. Reactive oxygen species were detected in 9-DDHC/UVA-exposed cells using the fluorescent probe 5-(and 6-)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester. Singlet oxygen was generated when 9-DDHC was UVA irradiated in CCl4. UVA irradiation of 9-DDHC in acetonitrile generated superoxide and carbon-centered and alkoxyl radicals which were trapped by 5,5-dimethyl-1-pyrroline N-oxide. These findings suggest that reactive oxygen species generated by 9-DDHC may play a role in the UVA skin photosensitivity of SLOS patients. Furthermore, several statin drugs inhibit 7-DHC reductase, in addition to hydroxymethylglutaryl-CoenzymeA reductase, so that 9-DDHC may also be responsible for statin-derived photosensitivity, dermatoses, and cataract formation. Finally, we have previously detected 9-DDHC in skin lipids from normal subjects, so this sterol may also be the skin chromophore responsible for skin photoaging and UV-induced skin cancer.
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The skin hypersensitivity seen in Smith-Lemli-Opitz syndrome patients is explained by reactive oxygen species-dependent formation of 5,7,9(10)-trienes.
“while the hypersensitivity of skin in SLOS patients has recently been explained by reactive oxigen species dependent formation of 5, 7, 9(10)-trienes.”
From Steroidogenesis in the skin: Implications for local immune functions (2013) · cites this paper as [158]
In Smith-Lemli-Opitz syndrome, deficiency of 7-dehydrocholesterol reductase leads to UVA photosensitivity of the skin and to formation of atypical steroids.
“Firstly, the 7-Δ reductase deficiency observed in Smith–Lemli–Opitz syndrome (SLOS), in an addition to severe malformations, results in development of skin photosensitivity to UVA [158, 159] and production a series of unusual steroids [79, 160, 161].”
From Steroidogenesis in the skin: Implications for local immune functions (2013) · cites this paper as [158]
Cholesta-5,7,9(11)-trien-3β-ol, a derivative of 7-dehydrocholesterol, is formed in skin exposed to UVA irradiation.
“It was shown that cholesta-5,7,9(11)-trien-3β-ol (9-DDHC) derivative of 7DHC is indeed formed in the skin subjected to UVA irradiation [158].”
From Steroidogenesis in the skin: Implications for local immune functions (2013) · cites this paper as [158]
9-DDHC can generate singlet oxygen in a UVR-stimulated cyclic reaction.
“Such a compound was capable of generating singlet oxygen in the cycle reaction stimulated by UVR [158, 165].”
From Steroidogenesis in the skin: Implications for local immune functions (2013) · cites this paper as [158]
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- Authors
- Chignell, C. F., Kukielczak, B. M., Sik, R. H., Bilski, P. J., & He, Y.-Y.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Chignell, Colin F.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 41
- Issue
- 2
- Pages
- 339-346
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2000239106
- Cited by
- 31
- References
- 30
- Citations by year
- 2025: 1 · 2023: 3 · 2022: 2 · 2018: 1 · 2017: 3 · 2016: 2 · 2014: 1 · 2013: 2 · 2012: 1
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- Smith-Lemli-Opitz syndrome, 7-dehydrocholesterol, DHCR7, cholesterol biosynthesis, phototoxicity, keratinocytes, reactive oxygen species, singlet oxygen, lipid peroxidation, AY-9944, skin lipids
- MeSH terms
- Animals, Cell Line, Cholestenes, Chromatography, High Pressure Liquid, Electron Spin Resonance Spectroscopy, Humans, Male, Spin Labels, Ultraviolet Rays, Keratinocytes, Reactive Oxygen Species, Smith-Lemli-Opitz Syndrome, Mice
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