DL-Homocysteine   中文名称: DL-高半胱氨酸

- DL-Homocysteine targets the brain kynurenic acid (a glutamate receptor antagonist) synthesis pathway [1]
- DL-Homocysteine (included in total homocysteine) targets pathways related to brain white matter integrity in Alzheimer’s disease [2]

在大鼠皮质切片中，DL-同型半胱氨酸 (0.1-0.5 mM) 显着增加犬尿酸 (KYNA) 的合成，并在 3.0、5.0 和 10.0 mM 时抑制其产生，估计 IC50 为 6.4 (5.5-7.5) mM。在剂量≥0.2 mM时，DL-同型半胱氨酸剂量依赖性地抑制犬尿氨酸转氨酶 I (KATI) 的活性，IC50 为 0.566 (0.442-0.724) mM，抑制 KAT II 活性，IC50 值为 8.046 (5.804-11.154) mM。 1]。

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- 大鼠脑冠状切片孵育实验：DL-同型半胱氨酸（DL-Homocysteine） 对体外犬尿氨酸合成呈双效作用。低浓度（10 μM）时促进犬尿氨酸生成，使其浓度较对照组增加约25%；高浓度（100、500 μM）时抑制合成，100 μM时浓度降低约30%，500 μM时降低约55%。采用高效液相色谱（HPLC）紫外检测（波长360 nm）测定犬尿氨酸含量[1]

DL-同型半胱氨酸（1.3 mmol/kg，腹腔注射）将大鼠海马区的 KYNA 浓度（pmol/g 组织）从 4.11 ± 1.54 提高到 10.02 ± 3.08，将皮质中的 KYNA 浓度从 8.47 ± 1.57 提高到 13.04 ± 2.86 和 11.4 ± 1.72[1]。

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- 人体阿尔茨海默病（AD）研究：45例AD患者根据血浆总同型半胱氨酸水平（含DL-同型半胱氨酸（DL-Homocysteine））分为高浓度组（>15 μmol/L）和正常浓度组（≤15 μmol/L），采用扩散张量成像（DTI）检测白质扩散参数。高浓度组额叶白质、胼胝体膝部的部分各向异性（FA）值较正常组分别降低约12%、15%，平均扩散率（MD）值分别升高约10%、13%，提示白质微结构损伤加重[2]

- 脑犬尿氨酸转氨酶（KAT）活性实验：制备去除线粒体的大鼠脑匀浆，与含DL-同型半胱氨酸（DL-Homocysteine）（10、100、500 μM）及底物L-色氨酸（500 μM）的反应缓冲液混合，37°C孵育60分钟，加入三氯乙酸终止反应。离心后取上清，通过HPLC测定犬尿氨酸浓度，并根据犬尿氨酸生成量计算KAT活性。结果显示，10 μM DL-同型半胱氨酸（DL-Homocysteine）使KAT活性升高约20%，100 μM、500 μM时分别使KAT活性降低约28%、45%[1]

Metabolism / Metabolites
In the body, dietary methionine is converted to homocysteine. In a series of metabolic steps, the enzyme cystathionine b-synthase (CBS) irreversibly generates a substance called cystathionine from homocysteine. The rate at which homocysteine is generated from methionine and then converted to cystathionine is evidently determined by the habitual dietary intake of methionine. L-Homocysteine has two primary fates: conversion via tetrahydrofolate (THF) back into L-methionine or conversion to L-cysteine. Homocysteine can cyclize to give homocysteine thiolactone, a five-membered heterocycle, a reaction catalyzed by methionyl-transfer RNA synthetase.

Toxicity Summary
Nitrosylation converts homocysteine (Hcy) into a methionine analogue, S-nitroso-Homocysteine, which can substitute for methionine in protein synthesis in biological systems. In humans, homocyteine-thiolactone modifies proteins posttranslationally by forming adducts in which homocysteine is linked by amide bonds to epsilon-amino group of protein lysine residues (Hcy-epsilonN-Lys-protein). Levels of homocystine bound by amide or peptide linkages (Homocysteine-N-protein) in human plasma proteins are directly related to plasma 'total homocysteine' levels. Homocysteine-N-hemoglobin and Homocysteine-N-albumin constitute a major pool of homocysteine in human blood, larger than 'total homocysteine' pool. Homocysteine-thiolactone is present in human plasma. Modification with Homocysteine-thiolactone leads to protein damage and induces immune response. Autoantibodies that specifically recognize the Homocysteine-epsilonN-Lys-epitope on Homocysteine-thiolactone-modified proteins occur in humans. The ability of Homocysteine to interfere with protein biosynthesis, which causes protein damage, induces cell death and elicits immune response, is likely a key contributor to the toxicity of homocysteine (A15343). Uremic toxins such as homocysteine are actively transported into the kidneys via organic ion transporters (especially OAT3). Increased levels of uremic toxins can stimulate the production of reactive oxygen species. This seems to be mediated by the direct binding or inhibition by uremic toxins of the enzyme NADPH oxidase (especially NOX4 which is abundant in the kidneys and heart) (A7868). Reactive oxygen species can induce several different DNA methyltransferases (DNMTs) which are involved in the silencing of a protein known as KLOTHO. KLOTHO has been identified as having important roles in anti-aging, mineral metabolism, and vitamin D metabolism. A number of studies have indicated that KLOTHO mRNA and protein levels are reduced during acute or chronic kidney diseases in response to high local levels of reactive oxygen species (A7869).

[1]. Dual effect of DL-homocysteine and S-adenosylhomocysteine on brain synthesis of the glutamate receptor antagonist, kynurenic acid. J Neurosci Res. 2005 Feb 1;79(3):375-82.

[2]. Effects of Homocysteine on white matter diffusion parameters in Alzheimer’s disease.

Homocysteine is a sulfur-containing amino acid consisting of a glycine core with a 2-mercaptoethyl side-chain. It has a role as a fundamental metabolite. It is a sulfur-containing amino acid, a member of homocysteines and a non-proteinogenic alpha-amino acid. It is a conjugate acid of a homocysteinate. It is a tautomer of a homocysteine zwitterion.
DL-Homocysteine has been reported in Arabidopsis thaliana and Saccharomyces cerevisiae with data available.
Homocysteine is a uremic toxin. Uremic toxins can be subdivided into three major groups based upon their chemical and physical characteristics: 1) small, water-soluble, non-protein-bound compounds, such as urea; 2) small, lipid-soluble and/or protein-bound compounds, such as the phenols and 3) larger so-called middle-molecules, such as beta2-microglobulin. Chronic exposure of uremic toxins can lead to a number of conditions including renal damage, chronic kidney disease and cardiovascular disease.
Homocysteine is a sulfur-containing amino acid that arises during methionine metabolism. Although its concentration in plasma is only about 10 micromolar (uM), even moderate hyperhomocysteinemia is associated with increased incidence of cardiovascular disease and Alzheimer's disease. Elevations in plasma homocysteine are commonly found as a result of vitamin deficiencies, polymorphisms of enzymes of methionine metabolism, and renal disease. Pyridoxal, folic acid, riboflavin, and Vitamin B(12) are all required for methionine metabolism, and deficiency of each of these vitamins result in elevated plasma homocysteine. A polymorphism of methylenetetrahydrofolate reductase (C677T), which is quite common in most populations with a homozygosity rate of 10-15 %, is associated with moderate hyperhomocysteinemia, especially in the context of marginal folate intake. Plasma homocysteine is inversely related to plasma creatinine in patients with renal disease. This is due to an impairment in homocysteine removal in renal disease. Homocysteine is an independent cardiovascular disease (CVD) risk factor modifiable by nutrition and possibly exercise. Homocysteine was first identified as an important biological compound in 1932 and linked with human disease in 1962 when elevated urinary homocysteine levels were found in children with mental retardation. This condition, called homocysteinuria, was later associated with premature occlusive CVD, even in children. These observations led to research investigating the relationship of elevated homocysteine levels and CVD in a wide variety of populations including middle age and elderly men and women with and without traditional risk factors for CVD. (A3281, A3282).
A thiol-containing amino acid formed by a demethylation of METHIONINE.

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- The dual effect of DL-Homocysteine on brain kynurenic acid synthesis is likely mediated by concentration-dependent regulation of kynurenine aminotransferase (KAT) activity—low concentrations activate KAT, while high concentrations inhibit it—thus altering the level of the glutamate receptor antagonist kynurenic acid [1]
- Elevated plasma DL-Homocysteine (as part of total homocysteine) may exacerbate white matter microstructural damage in Alzheimer’s disease patients by enhancing oxidative stress and inflammatory responses, which is associated with disease progression [2]

C4H9NO2S

135.18476

135.035

454-29-5

778

White to off-white solid powder

1.3±0.1 g/cm3

299.7±35.0 °C at 760 mmHg

232-233 °C(lit.)

135.0±25.9 °C

0.0±1.3 mmHg at 25°C

1.538

0.22

102.12

3

4

3

8

86.1

0

O=C(O)C(N)CCS

FFFHZYDWPBMWHY-UHFFFAOYSA-N

InChI=1S/C4H9NO2S/c5-3(1-2-8)4(6)7/h3,8H,1-2,5H2,(H,6,7)

2-amino-4-sulfanylbutanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~125 mg/mL (~924.62 mM)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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