The metabolism of Vitamin D3 by human liver microsomes and its inter-individual differences文献综述

 2022-12-25 12:25:37

开题报告内容：（包括拟研究或解决的问题、采用的研究手段及文献综述，不少于2000字）

Vitamin D summary

Vitamin D is a steroid hormone which is required for normal calcium and phosphorus metabolism. Vitamin D deficiency is associated with osteoporosis and is thought to increase the risk of cancer and CVD[1]. More recently, vitamin D status has been linked to cardiovascular disease, autoimmune disease and infection. The major source of vitamin D effects in humans is from vitamin D3, which is initially converted to 25-hydroxyvitamin D3(25OHD3) in the liver[2]. 25OHD3 is the predominant circulating form of this important vitamin and it can be metabolized to 1,25(OH)2D in the kidney, which is the biologically active form of vitamin D3 and plays an essential role in calcium and phosphorus homeostasis. Insufficiency or deficiency of 25OHD3 could lead to metabolic bone diseases, such as rickets, osteoporosis, and osteomalacia[3–5]. There is significant variability in the estimates of plasma/serum 25(OH)D levels across observational studies, with mean and median values ranging from 4·9 to 136·2 nmol/l and 20·7 to 91·0 nmol/l, respectively[1]. Although both genetic variation and environmental factors are associated with 25OHD3 levels, most of the variability is unexplained. However, almost half of the genetic studies conducted are based on European populations, followed by Asian and North American, which introduce bias for which variants or environmental factors are important.

Production and metabolism of Vitamin D

The body gets vitamin D3 from sunlight exposure to the skin and in the diet. When the skin is exposed to sunlight, 7-dehydrocholesterol absorbs UVB radiation and the energy causes chemical bonds within the molecule to break and rearrange, resulting in the formation of previtamin D3. In the skin, previtamin D3 undergoes rapid thermally-induced transformation to vitamin D3[6]. Dietary vitamin D3 is absorbed from the gut in the form of mixed micelles and then chylomicrons, which then release vitamin D3 to the circulation. Circulating vitamin D3 is metabolized in the liver to 25OHD3 and this form of vitamin D is often measured by clinicians wishing to assess vitamin D status. However, it has to be further oxidized at the 1-position by the enzyme CYP27B1 to 1,25-dihydroxyvitamin D3 (1alpha;,25-(OH)2D3) to become fully active and regulate gene transcription and cell function(Figure.1). It is well-known that the activation of vitamin D3 require 25-hydroxylation in the liver and 1alpha;-hydroxylation in the kidney. However, people know little about the enzymes which can hydroxylate vitamin D at 25 position.

Figure.1 The Role of the Parent Compound Vitamin D with Respect to Metabolism and Function[7]

CYP2R1 SUMMARY

In 1998, Bjouml;rkhem et al. successfully developed a method to detect 25OHD3 generated from vitamin D3 by purified rat liver microsomal and proved that there is a typical cytochrome P-450 (CYP) that can catalyze the reaction[8]. However, there is some controversy about which CYP is the most important 25-hydroxylase. Though mitochondrial CYP27A1 is a vitamin D3 25-hydroxylase, researchers found that mice with disrupted a CYP27A1 gene showed markedly reduced bile acid biosynthesis, with the plasma level of 25-hydroxyvitamin D3 increasing more than 2-fold[9], in contrast to expectations. Recently, human CYP2R1 has been reported to be a potential candidate for a hepatic vitamin D 25-hydroxylase. Rosen et al.[9] and Cheng et al.[10] have succeed in the functional expression of human CYP2R1 in HEK 293 cells and detected 25-hydroxylation activity toward vitamin D3, 1alpha;(OH)D3. They also reported that the CYP2R1 mutant L99P eliminated vitamin D 25-hydroxylase activity and that this mutation of CYP2R1 enzyme causes selective 25-hydroxyvitamin D3 deficiency, which are quite strong evidence that CYP2R1 is a physiologically important vitamin D 25- hydroxylase. After them, Raku et al. compared the function of CYP27A1 and CYP2R1 using microsomal fractions from the recombinant cells expressing these two enzymes, respectively. They found that CYP2R1 hydroxylated vitamin D2 at the C-25 position while CYP27A1 hydroxylated it at position of C-24 and C-27[11].Cheng et al. revealed detailed enzymatic properties of human CYP2R1 using a yeast expression system and recombinant CYP2R1 showed 25-hydroxylation activity towards vitamin D3, as reportedly previously. Purified CYP2R1 can convert membrane-associated vitamin D3 to 25(OH)D3, and its catalytic efficiency is 17-fold higher than CYP27A1. CYP2R1 converted vitamin D3 in the vesicle membrane to 25-hydroxyvitamin D3 [25(OH)D3] with good adherence to Michaelis-Menten kinetics[12].

Considering the low concentration of CYP2R1 in liver microsomes and the poor solubility of vitamin D3 in water, most researchers choose to make purified enzyme expressing system to characterize the function of CYP2R1. Cheng et al. investigated different systems for the addition of substrates to CYP2R1, via stock solutions in ethanol or 2-hydroxypropyl-beta;-cyclodextrin (HP-beta;-CD), or incorporated into the membrane of phospholipid vesicles. The results showed that addition of vitamin D3 from an ethanol stock, as employed in previous studies on CYP2R1, displayed the highest conversion to 25(OH)D3, while addition from HP-beta;-CD displayed the lowest[12].

剩余内容已隐藏，您需要先支付 10元 才能查看该篇文章全部内容！立即支付

发小红书推广免费获取该资料资格。点击链接进入获取推广文案即可： Ai一键组稿 | 降AI率 | 降重复率 | 论文一键排版

您可能感兴趣的文章