Lumisterol is metabolized by CYP11A1: discovery of a new pathway.
Lumisterol is metabolized by CYP11A1: discovery of a new pathway.
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DOI：
10.1016/j.biocel.2014.08.004
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发表时间：
2014-10
影响因子：
4
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Tuckey, Robert C.;Slominski, Andrzej T.;Cheng, Chloe Y. S.;Chen, Jianjun;Kim, Tae-Kang;Xiao, Min;Li, Wei
Lumisterol 3（L3）是在暴露于高剂量紫外线B辐射期间，通过7-脱氢胆固醇（7-DHC）的光化学转化产生的。据推测，L3在生物学上是无活性的，在体内不会代谢。然而，L3的一些合成衍生物显示出生物活性。本研究的目的是检测CYP 11 A1代谢L3的能力。L3与牛或人CYP 11 A1孵育导致形成三种主要产物和许多次要产物。牛CYP 11 A1对溶于2-羟丙基-β-环糊精的L3代谢的催化效率约为维生素D3和胆固醇的20%。通过核磁共振谱鉴定了三个主要产物的结构，分别为24-羟基-L3、22-羟基-L3和20，22-二羟基-L3。22-羟基-L3通过牛CYP 11 A1进一步代谢为20，22-二羟基-L3。22-羟基-L3和20，22-二羟基-L3均产生一种次要代谢产物，经真实标准品和质谱鉴定为阿鲁甾醇（pL）（L3的C20-C22侧链裂解产物）和两种三羟基-L3产物。使用猪肾上腺片段证明了表达CYP 11 A1的组织代谢L3的能力，其中通过LC/MS检测到20，22-二羟基-L3、22-羟基-L3、24-羟基-L3和pL。因此，我们已经确定L3被CYP 11 A1代谢为22-和24-羟基-L3以及20，22-二羟基-L3作为主要产物，以及pL和其他次要产品。先前报道的生物活性的pL和CYP 11 A1在皮肤中的存在表明，该途径可能有助于从L3产生生物活性产物，强调了CYP 11 A1在甾醇代谢中的新作用。
Lumisterol3 (L3) is produced by photochemical transformation of 7-dehydrocholesterol (7-DHC) during exposure to high doses of ultraviolet B radiation. It has been assumed that L3 is biologically inactive and is not metabolized in the body. However, some synthetic derivatives of L3 display biological activity. The aim of this study was to test the ability of CYP11A1 to metabolize L3. Incubation of L3 with bovine or human CYP11A1 resulted in the formation of three major and a number of minor products. The catalytic efficiency of bovine CYP11A1 for metabolism of L3 dissolved in 2-hydroxypropyl-β-cyclodextrin was approximately 20% of that reported for vitamin D3 and cholesterol. The structures of the three major products were identified as 24-hydroxy-L3, 22-hydroxy-L3 and 20,22-dihydroxy-L3 by NMR. 22-hydroxy-L3 was further metabolized by bovine CYP11A1 to 20,22-dihydroxy-L3. Both 22-hydroxy-L3 and 20,22-dihydroxy-L3 gave rise to a minor metabolite identified from authentic standard and mass spectrometry as pregnalumisterol (pL) (product of C20-C22 side chain cleavage of L3) and two trihydroxy-L3 products. The capability of tissues expressing CYP11A1 to metabolize L3 was demonstrated using pig adrenal fragments where 20,22-dihydroxy-L3, 22-hydroxy-L3, 24-hydroxy-L3 and pL were detected by LC/MS. Thus, we have established that L3 is metabolized by CYP11A1 to 22- and 24-hydroxy-L3 and 20,22-dihydroxy-L3 as major products, as well as to pL and other minor products. The previously reported biological activity of pL and the presence of CYP11A1 in skin suggest that this pathway may serve to produce biologically active products from L3, emphasizing a novel role of CYP11A1 in sterol metabolism.
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影响因子：
3.3
作者：
Dixon, Katie M.;Norman, Anthony W.;Mason, Rebecca S.
通讯作者：
Mason, Rebecca S.
影响因子：
3.7
作者：
Slominski AT;Janjetovic Z;Fuller BE;Zmijewski MA;Tuckey RC;Nguyen MN;Sweatman T;Li W;Zjawiony J;Miller D;Chen TC;Lozanski G;Holick MF
通讯作者：
Holick MF
影响因子：
5.8
作者：
Slominski, Andrzej;Janjetovic, Zorica;Postlethwaite, Arnold E.
通讯作者：
Postlethwaite, Arnold E.
影响因子：
56.9
作者：
HOLICK, MF;MACLAUGHLIN, JA;DOPPELT, SH
通讯作者：
DOPPELT, SH
影响因子：
--
作者：
Slominski, A;Semak, I;Tuckey, RC
通讯作者：
Tuckey, RC