School of Molecular Sciences, The University of Western Australia, Perth, WA, 6009, Australia.
School of Molecular Sciences, The University of Western Australia, Perth, WA, 6009, Australia.
J Steroid Biochem Mol Biol. 2019 Feb;186:4-21. doi: 10.1016/j.jsbmb.2018.09.003. Epub 2018 Sep 8.
Vitamin D, referring to the two forms, D2 from the diet and D3 primarily derived from phototransformation in the skin, is a prohormone important in human health. The most hormonally active form, 1α,25-dihydroxyvitamin D (1α,25(OH)D), formed from vitamin D via 25-hydroxyvitamin D (25(OH)D), is not only important for regulating calcium metabolism, but has many pleiotropic effects including regulation of the immune system and has anti-cancer properties. The major circulating form of vitamin D is 25(OH)D and both D2 and D3 forms are routinely measured by LC/MS/MS to assess vitamin D status, due to their relatively long half-lives and much higher concentrations compared to 1α,25(OH)D. Inactivation of both 25(OH)D and 1α,25(OH)D is catalyzed by CYP24A1 and 25-hydroxyvitamin D3 3-epimerase. Initial products from these enzymes acting on 25(OH)D3 are 24R,25(OH)D3 and 3-epi-25(OH)D3, respectively, and both of these can also be measured routinely in some clinical laboratories to further document vitamin D status. With advances in LC/MS/MS and its increased availability, and with the help of studies with recombinant vitamin D-metabolizing enzymes, many other vitamin D metabolites have now been detected and in some cases quantitated, in human serum. CYP11A1 which catalyzes the first step in steroidogenesis, has been found to also act on vitamins D3 and D2 hydroxylating both at C20, but with some secondary metabolites produced by subsequent hydroxylations at other positions on the side chain. The major vitamin D3 metabolite, 20S-hydroxyvitamin D3 (20S(OH)D3), shows biological activity, often similar to 1α,25(OH)D3 but without calcemic effects. Using standards produced enzymatically by purified CYP11A1 and characterized by NMR, many of these new metabolites have been detected in human serum, with semi-quantitative measurement of 20S(OH)D3 indicating it is present at comparable concentrations to 24R,25(OH)D3 and 3-epi-25(OH)D3. Recently, vitamin D-related hydroxylumisterols derived from lumisterol3, a previtamin D3 photoproduct, have also been measured in human serum and displayed biological activity in initial in vitro studies. With the current extensive knowledge on the reactions and pathways of metabolism of vitamin D, especially those catalyzed by CYP24A1, CYP27A1, CYP27B1, CYP3A4 and CYP11A1, it is likely that many other of the resulting hydroxyvitamin D metabolites will be measured in human serum in the future, some contributing to a more detailed understanding of vitamin D status in health and disease.
维生素 D 包括两种形式，D2 来自饮食，D3 主要来自皮肤中的光转化，是一种在人类健康中重要的前激素。最具激素活性的形式，1α,25-二羟基维生素 D（1α,25(OH)D），由维生素 D 通过 25-羟维生素 D（25(OH)D）形成，不仅对调节钙代谢很重要，而且具有许多多效性作用，包括调节免疫系统和具有抗癌特性。维生素 D 的主要循环形式是 25(OH)D，D2 和 D3 形式都通过 LC/MS/MS 常规测量，以评估维生素 D 状态，因为它们的半衰期相对较长，与 1α,25(OH)D 相比，浓度要高得多。CYP24A1 和 25-羟维生素 D3 3-差向异构酶催化 25(OH)D 和 1α,25(OH)D 的失活。这些酶作用于 25(OH)D3 的初始产物分别是 24R,25(OH)D3 和 3-差向-25(OH)D3，这两者都可以在一些临床实验室中常规测量，以进一步记录维生素 D 状态。随着 LC/MS/MS 的进步及其可用性的提高，以及借助具有重组维生素 D 代谢酶的研究，现在已经在人血清中检测到并在某些情况下定量了许多其他维生素 D 代谢物。催化类固醇生物合成第一步的 CYP11A1 已被发现也作用于维生素 D3 和 D2，在 C20 羟基化，但在侧链的其他位置随后羟基化会产生一些次级代谢物。主要的维生素 D3 代谢物，20S-羟基维生素 D3（20S(OH)D3）具有生物活性，通常类似于 1α,25(OH)D3，但没有钙调作用。使用通过纯化的 CYP11A1 酶促产生并通过 NMR 表征的标准品，已经在人血清中检测到了许多这些新的代谢物，并对半定量测量 20S(OH)D3 表明其存在的浓度与 24R,25(OH)D3 和 3-差向-25(OH)D3 相当。最近，来自 previtamin D3 光产物 lumisterol3 的维生素 D 相关羟基甾醇也已在人血清中进行了测量，并在最初的体外研究中显示出生物活性。鉴于目前对维生素 D 代谢的反应和途径有广泛的了解，特别是由 CYP24A1、CYP27A1、CYP27B1、CYP3A4 和 CYP11A1 催化的途径，很可能在未来会在人血清中测量到许多其他的羟基维生素 D 代谢物，其中一些有助于更详细地了解健康和疾病中维生素 D 的状态。
