UV-induced Melanin Chemiexcitation: A New Mode of Melanoma Pathogenesis.
UV-induced Melanin Chemiexcitation: A New Mode of Melanoma Pathogenesis.
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DOI：
10.1177/0192623316632072
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发表时间：
2016-06
影响因子：
1.5
通讯作者：
Brash DE
中科院分区：
文献类型：
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作者：
Brash DE
在阳光诱导的黑色素瘤中的突变来自环丁烷嘧啶二聚体（CPD），DNA光产物通常在紫外线（UV）光子被胸腺嘧啶或胞嘧啶吸收后皮秒产生。令人惊讶的是，我们发现，在黑素细胞中，CPD在UVA或UVB暴露后数小时产生。这些“深色CPD”构成了培养的人类和小鼠黑素细胞以及小鼠皮肤中的大多数CPD，并且它们在含有褐黑素的皮肤中最为突出，褐黑素是负责金色和红色毛发的黑色素。机制也是一个惊喜。当紫外线诱导超氧化物和一氧化氮联合收割机结合形成过氧亚硝酸盐时，产生暗CPD。过氧亚硝酸盐是少数能够激发电子的生物分子之一。这个过程称为“化学激发”，是低等生物发光的来源。激发发生在黑色素的碎片中，产生一个量子三重态，具有紫外光子的能量，但通过无辐射能量转移到DNA来诱导CPD。UVA和过氧亚硝酸盐也溶解了黑色素并渗透了核膜，使黑色素进入。黑色素显然具有致癌性和保护性。化学激发也可能引发内部组织的发病机制，因为在含有黑色素的细胞附近产生超氧化物和一氧化氮的地方也会产生相同的化学物质。
Mutations in sunlight-induced melanoma arise from cyclobutane pyrimidine dimers (CPDs), DNA photoproducts usually created picoseconds after an ultraviolet (UV) photon is absorbed at thymine or cytosine. Surprisingly we found that, in melanocytes, CPDs were generated for hours after UVA or UVB exposure. These “dark CPDs” constituted the majority of CPDs in cultured human and murine melanocytes and in mouse skin, and they were most prominent in skin containing pheomelanin, the melanin responsible for blonde and red hair. The mechanism was also a surprise. Dark CPDs arise when UV-induced superoxide and nitric oxide combine to form peroxynitrite, one of the few biological molecules capable of exciting an electron. This process, termed “chemiexcitation”, is the source of bioluminescence in lower organisms. Excitation occurred in fragments of melanin, creating a quantum triplet state that had the energy of a UV photon but which induced CPDs by radiationless energy transfer to DNA. UVA and peroxynitrite also solubilized melanin and permeabilized the nuclear membrane, allowing melanin to enter. Melanin is evidently carcinogenic as well as protective. Chemiexcitation may also trigger pathogenesis in internal tissues because the same chemistry should arise wherever superoxide and nitric oxide arise near cells that contain melanin.