Tuesday, September 16, 2008

Comments on the Photo-protective qualities of epidermal Melanin Content of skin

Based on extracts from Yamaguchi et al. 2006, we have the following:

— DNA damage in the upper epidermis immediately after UV exposure was similar among racial/ethnic groups but levels of DNA damage in the lower concentration of the epidermis was inversely proportional to the melanin content.

Courtesy of Yamaguchi et al. 2006: Figure 1. A) Representative images of CPD DNA damage in fair, intermediate and dark skin immediately and 7 d after UV exposure; green and red fluorescence represent CPD and DNA, respectively. (———) demarks the top of the granular layer of the epidermis, (- - - -) demarks the epidermal:dermal junction, and (· · · · ·) represents the division between the upper and lower epidermal layers. B) Representative images of CPD (green) in melanocytes (stained red for tyrosinase) immediately after UV in fair, intermediate and dark skin.

— Pulse lasers cause highly selective injury to cells containing melanosomes suggesting that the UV energy absorbed by melanin in the upper epidermis causes photothermolysis (heat damage) to pigmented cells.

— The oncogene p53 plays important roles in responses to UV-induced DNA damage and induction of DNA repair. There is an overall nuclear accumulation of p53 in response to UV. More than 13 sites of p53 are known to be phosphorylated, one of them being a critical site at Ser-46, which is associated with the induction of apoptosis.

More p53 accumulated in the nuclei of cells in fair skin than in dark skin at 1 d and at 7 d after UV exposure. However, phosphorylation of p53 at Ser-46 was not seen in fair skin, whereas it was readily seen in dark skin 1 d after UV exposure…

Phosphorylation of p53 at Ser-46, which is associated with the induction of apoptosis, occurred at low levels in fair skin after low doses of UV exposure but was significant in dark skin, suggesting that p53 phosphorylation site is involved in UV-induced apoptosis in epidermis with abundant levels of melanin.

TUNEL assays showed that significantly more apoptotic cells were found in Black skin equivalents than in Asian or White skin equivalents at both UV doses...

nuclear accumulation of p53 is less in dark skin than in fair skin, suggesting that the overall activation of p53 following UV-induced DNA damage is greater in fair skin. The sustained activation of p53 may also in part cause the higher incidence of photo carcinogenesis in fair skin.

melanin content is responsible for the apoptosis. Cells containing melanin in the upper epidermis of dark skin tended to undergo more apoptosis after UV than do those of fair skin. Thus, the presence of melanin facilitates the apoptotic effect of UV on cells but whether that results from photothermolysis or whether other properties of melanins are involved will require further study.

DNA damage in the upper epidermis immediately after UV exposure was similar among racial/ethnic groups but levels of DNA damage in the lower concentration of the epidermis was inversely proportional to the melanin content.
Taken together,…

— UV-induced DNA damage in the lower epidermis (which contains keratinocyte stem cells and melanocytes) is not effectively prevented in fair skin because of the low melanin content in the upper (and lower) epidermis.

DNA damage in the upper epidermis is quite similar among all types of skin, which indicates that epidermal pigmentation is an efficient UV filter for underlying cells.

— UV-induced apoptosis was virtually absent in fair skin after low UV doses, but was significant in dark skin, facilitating the effective removal of UV-damaged cells in dark skin.

— Virtually all epidermal cells had significant DNA damage in fair skin but only ~1% of them became apoptotic whereas less than 50% of epidermal cells in dark skin had significant DNA damage, yet ~ 5% of those cells were apoptotic.

— The combination of relatively low DNA damage and efficient removal of UV-damaged cells contributes to the decreased incidence of skin cancer in darker skin.

we conclude that the upper epidermis of dark skin is significantly more photoprotective for the deeper tissue against UV damage than that of fair skin.

And now, on the understanding gleaned from the above, some personal observations about the photo-protective qualities of epidermal melanin content:

Essentially, the side effect of UV-radiation damage of DNA in epidermal cells is the activation of the p53 gene to presumably suppress cell division of damaged DNA, and allow for repair, which would explain the accumulation of this type in cell nuclei after UV exposure. However, given the greater DNA damage in fair skin due to reduced melanin content, more p53 are activated than the case is for dark skin; the other problem here though, seems to be that there is also a strong correlation between the phosphorylation of p53 at the Ser-46 locus of the gene, which appears to be critical for apoptosis, and epidermal melanin content; the greater the epidermal melanin, the greater chances of greater occurrence of nuclear p53 genes phosphorylated at their Ser-46 locus. The precise triggering aspect of melanin on apoptosis is something that is subject to further investigation, according to Yamaguchi et al.: the presence of melanin facilitates the apoptotic effect of UV on cells but whether that results from photothermolysis or whether other properties of melanins are involved will require further study.

Since this development [phosphorylation] at the Ser-46 locus appears to be much rarer on p53 genes in epidermal cells of fair skin, the prospect of apoptosis occurring after UV exposure is substantially lower, if not rare. This means that damaged DNA are allowed to spread via cell division and so, defects being passed onto daughter cells; on the other hand, greater presence of phosphorylation of the p53 gene at its Ser-46 locus in dark skin epidermal cells allows for effective removal of UV-induced damaged DNA. So, it would appear that the hindrance of p53 gene in fair skin epidermal cells to play a role in removal of cells containing damaged DNA in the process of assisting in DNA repair, at least in part, interrupts the optimal balance between cell division and apoptosis, thereby contributing to photo-carcinogenesis. [see: Yamaguchi et al. 2006; Human skin responses to UV radiation: Pigment in the upper epidermis protects against DNA damage in the lower epidermis and facilitates apoptosis]
_____________________________________________________________
*Related reading:

Skin pigmentation gene alleles

Skin pigmentation gene alleles — Part 2

No comments: