The Role of Overirradiation Products of Vitamin D in Photoprotection
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USyd Access
Type
ThesisThesis type
Doctor of PhilosophyAbstract
The hormonal form of vitamin D, 1,25(OH)2D3, reduces UV-induced DNA damage. Cutaneous vitamin D is produced by UV. Continued UV exposure photoisomerises pre-vitamin D3 to produce ‘overirradiation products’ such as lumisterol3. Cytochrome P450 side chain cleavage enzyme in skin ...
See moreThe hormonal form of vitamin D, 1,25(OH)2D3, reduces UV-induced DNA damage. Cutaneous vitamin D is produced by UV. Continued UV exposure photoisomerises pre-vitamin D3 to produce ‘overirradiation products’ such as lumisterol3. Cytochrome P450 side chain cleavage enzyme in skin catalyzes lumisterol3 to produce three main derivatives; 24(OH)L3 , 22(OH)L3 and 20,22(OH)2L3 . Whether the major overirradation metabolite, 24(OH)L3, contributes to photoprotection is unknown. In human primary keratinocytes treatment with 24(OH)L3, immediately after irradiation, reduced UV-induced DNA damage, CPD and 8-OHdG . In Skh:hr1 mice topical 24(OH)L3 reduced UV-induced DNA damage, inflammation and immune suppression after acute UV exposure, but was not as effective as 1,25(OH)2D3 against photocarcinogenesis. How 24(OH)L3 or the index compound 1,25(OH)2D3 actually reduce DNA damage, or even whether this is due to enhanced DNA repair is unknown. The studies showed that, like 1,25(OH)2D3, 24(OH)L3 increased DNA repair. This increased repair was in part due to increased availability of energy from glycolysis after UV. A novel assay whole cell ELISA for PARP activity was developed. It showed that both 1,25(OH)2D3 and 24(OH)L3 suppressed PARP activity. Since PARP-1 suppresses glycolysis, this action of the vitamin D-related compounds is likely to contribute to enhanced DNA repair. Like 1,25(OH)2D3, 24(OH)L3 and other vitamin D-like compounds require the vitamin D receptor and endoplasmic reticulum protein57 and also require the presence of DNA damage recognition proteins, XPC , DDB2 and XPA to reduce UV-induced DNA damage. Both 1,25(OH)2D3 and 24(OH)L3 increase in skin after UV exposure and may both contribute to endogenous photoprotection.
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See moreThe hormonal form of vitamin D, 1,25(OH)2D3, reduces UV-induced DNA damage. Cutaneous vitamin D is produced by UV. Continued UV exposure photoisomerises pre-vitamin D3 to produce ‘overirradiation products’ such as lumisterol3. Cytochrome P450 side chain cleavage enzyme in skin catalyzes lumisterol3 to produce three main derivatives; 24(OH)L3 , 22(OH)L3 and 20,22(OH)2L3 . Whether the major overirradation metabolite, 24(OH)L3, contributes to photoprotection is unknown. In human primary keratinocytes treatment with 24(OH)L3, immediately after irradiation, reduced UV-induced DNA damage, CPD and 8-OHdG . In Skh:hr1 mice topical 24(OH)L3 reduced UV-induced DNA damage, inflammation and immune suppression after acute UV exposure, but was not as effective as 1,25(OH)2D3 against photocarcinogenesis. How 24(OH)L3 or the index compound 1,25(OH)2D3 actually reduce DNA damage, or even whether this is due to enhanced DNA repair is unknown. The studies showed that, like 1,25(OH)2D3, 24(OH)L3 increased DNA repair. This increased repair was in part due to increased availability of energy from glycolysis after UV. A novel assay whole cell ELISA for PARP activity was developed. It showed that both 1,25(OH)2D3 and 24(OH)L3 suppressed PARP activity. Since PARP-1 suppresses glycolysis, this action of the vitamin D-related compounds is likely to contribute to enhanced DNA repair. Like 1,25(OH)2D3, 24(OH)L3 and other vitamin D-like compounds require the vitamin D receptor and endoplasmic reticulum protein57 and also require the presence of DNA damage recognition proteins, XPC , DDB2 and XPA to reduce UV-induced DNA damage. Both 1,25(OH)2D3 and 24(OH)L3 increase in skin after UV exposure and may both contribute to endogenous photoprotection.
See less
Date
2019-01-01Licence
The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.Faculty/School
Faculty of Medicine and HealthDepartment, Discipline or Centre
Discipline of PhysiologyAwarding institution
The University of SydneyShare