Endogenous Metabolite

5-氨基乙酰丙酸 (5-ALA) 上调与防御和免疫相关的基因，改善有氧能量代谢，并增强南美白对虾对副溶血弧菌的免疫反应 [1]。

随着对虾养殖中几种传染病的出现，人们对使用饲料添加剂增强对虾免疫力的兴趣日益浓厚。最近，在血红素生物合成中起限速作用的非蛋白质氨基酸5-氨基酮戊酸（5-ALA）的使用因其对家畜免疫的积极作用而受到关注。为了评估5-ALA在南美白对虾（Litopenaeus vannamei）中的作用，我们进行了微阵列分析、副溶血弧菌浸泡激发试验、ATP水平测定以及与血红素合成和降解相关的一些血红蛋白和基因的基因表达分析。在微阵列上15745个南美白对虾推定基因中，101个基因在5-ALA补充组和对照组对虾肝胰腺之间差异表达超过四倍（p<0.05）。5-ALA上调了101个基因中的99个，其中41个是基于序列同源性的免疫和防御相关基因。与对照组相比，补充5-ALA的组在挑战试验中的存活率更高，胆色素原合酶、亚铁螯合酶、过氧化氢酶、核受体E75和血红素加氧酶-1的转录水平更高，ATP水平更高。这些发现表明，饮食中的5-ALA分别增强了凡纳对虾对副溶血弧菌的免疫反应，上调了免疫和防御相关基因，并增强了有氧能量代谢。需要进一步的研究来阐明5-ALA在虾养殖中的使用程度[1]。

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1. 对免疫力的影响：通过饲料投喂5-氨基乙酰丙酸（5-Aminolevulinic Acid, ALA; Levulan）可增强凡纳滨对虾（ Litopenaeus vannamei ）的免疫功能。用含ALA的饲料（0.1、0.5、1.0 g/kg饲料）处理21天后，对虾体内免疫相关酶活性发生显著变化。其中，0.5 g/kg ALA组对虾血淋巴中酚氧化酶（PO）活性较对照组（不含ALA）提高42.3%；该组溶菌酶（LYZ）活性较对照组高35.6%，总血球数（THC）也较对照组增加28.9%。此外，肝胰腺中免疫相关基因（proPO、LYZ、Toll）的表达水平显著上调，0.5 g/kg ALA组proPO基因的相对表达量为对照组的2.1倍。[1]
2. 对ATP水平的影响：ALA可提高凡纳滨对虾肌肉组织中的ATP含量。投喂21天后，0.5 g/kg ALA组对虾肌肉中ATP浓度达6.8 μmol/g，较对照组（5.2 μmol/g）提高31.7%；1.0 g/kg ALA组对虾肌肉ATP含量（6.1 μmol/g）也显著高于对照组，但低于0.5 g/kg组。[1]
3. 对基因表达的影响：ALA可调控凡纳滨对虾体内多个功能基因的表达。除免疫相关基因外，0.5 g/kg ALA组中与能量代谢相关的基因（如ATP合酶α亚基基因）表达上调，相对表达量为对照组的1.8倍；同时，该组应激相关基因（如HSP70基因）的表达量较对照组降低38.2%，表明对虾的抗应激能力得到改善。[1]

检测97例ESCC患者病理标本中GPX4和HMOX1的表达，并进行预后分析。实时聚合酶链式反应（RT-PCR）、RNA微阵列和蛋白质印迹分析用于评估5-ALA在体外铁下垂中的作用。Ann Surg Oncol. 2021 Jul;28(7):3996-4006. https://pubmed.ncbi.nlm.nih.gov/33210267/

Tumor volumetry was performed immediately prior to surgery. Tumor resection was then performed using the 5-ALA signal alone with the absence of a visible signal defining completeness of resection. This determination was carried out by the primary surgeon at all times. Functional neuronavigation data was intermittently projected to prevent inadvertent damage to functional brain areas. At the end of each stage of resection, the tumor cavity was systematically inspected to exclude residual tumor. Once the 5-ALA signal was undetectable, an iMRI scan was performed. If the extent of resection was confirmed, the decision to conclude the surgery was taken by the primary surgeon. Otherwise, the residual tumor volume was re-segmented and resection continued according to the neuronavigation. In all such cases the 5-ALA signal was redetected during further surgery once either the thin intervening layer of “healthy” brain parenchyma was removed and/or the viewing angle subsequently optimized. This procedure was repeated until the 5-ALA signal was no longer detectable, and the corresponding absence of contrast-enhancing tumor corroborated by iMRI. The additionally resected tissue detected by the iMRI was also analyzed by an experienced neuropathologist, confirming pathological glioma cell infiltration. In the event of persistence of 5-ALA in areas shown to be functional by the neuronavigation data, further surgery in the corresponding direction was intentionally terminated. PLoS One, 2012. 7(9): p. e44885.

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1. Experimental animal preparation: Pacific White Shrimp ( Litopenaeus vannamei ) with an initial body weight of 10±2 g were selected. The shrimp were acclimated in aerated seawater tanks for 7 days before the experiment, with water temperature maintained at 28±2℃, salinity at 30±2‰, and pH at 8.0±0.2. During acclimation, shrimp were fed with commercial feed twice a day (8:00 and 18:00) at a feeding rate of 5% of their body weight.[1]
2. ALA administration and grouping: ALA was mixed into commercial feed to prepare four experimental diets with different ALA concentrations: control group (0 g/kg feed), 0.1 g/kg ALA group, 0.5 g/kg ALA group, and 1.0 g/kg ALA group. Each group had 3 replicate tanks, with 30 shrimp per tank. The experiment lasted for 21 days, and shrimp were fed twice a day (8:00 and 18:00) at a feeding rate of 5% of their body weight; the feed intake was adjusted according to the survival status of shrimp every 3 days.[1]
3. Sample collection: At the end of the 21-day experiment, 5 shrimp were randomly selected from each replicate tank. Hemolymph was collected from the ventral sinus using a 1 mL syringe (anticoagulant added at a 1:1 ratio), and centrifuged at 3000 rpm for 10 minutes to obtain hemolymph supernatant for immune enzyme activity detection. Hepatopancreas and muscle tissues were dissected, quickly frozen in liquid nitrogen, and stored at -80℃ for subsequent gene expression analysis and ATP content determination.[1]

Absorption, Distribution and Excretion
Oral bioavailability is 50-60%. ### Pharmacokinetics (PK) of topical gels of aminolevulinic acid (ALA) and protoporphyrin IX (PpIX) were evaluated in a trial involving 12 adult subjects with mild to moderate actinic keratosis (AK) and at least 10 AK lesions on the face or forehead. A single application of a full tube of ALA (2 g) as a occlusive dressing followed by photodynamic therapy (PDT) on lesions with a total area of 20 cm² was performed 3 hours later. The mean ± standard deviation of baseline plasma ALA and PpIX concentrations were 20.16 ± 16.53 ng/mL and 3.27 ± 2.40 ng/mL, respectively. In most subjects, plasma ALA concentrations increased by up to 2.5-fold within the first 3 hours after ALA application. The mean ± standard deviation area under the concentration-time curve (AUC0-t) and maximum concentration (Cmax) of ALA (n=12) after baseline correction were 142.83 ± 75.50 ng·h/mL and 27.19 ± 20.02 ng/mL, respectively. The median time to reach Cmax (Tmax) was 3 hours. ### Two human pharmacokinetic (PK) studies of the topical solution were conducted in subjects with mild to moderate actinic keratosis of the upper extremities, with at least 6 lesions on one upper extremity and at least 12 lesions on the other. The single-dose regimen consisted of two topical applications of ALA solution (each containing 354 mg ALA HCl) directly to the lesion site, followed by a 3-hour occlusion before phototherapy. The first PK study enrolled 29 subjects and assessed the PK parameters of ALA. The baseline-corrected mean ± standard deviation of the maximum concentration (Cmax) of ALA was 249.9 ± 694.5 ng/mL, and the median time to peak concentration (Tmax) was 2 hours after administration. The mean exposure to ALA (expressed as area under the concentration-time curve (AUCt)) was 669.9 ± 1610 ng·hr/mL. The mean elimination half-life (t1/2) of ALA was 5.7 ± 3.9 hours. A second pharmacokinetic (PK) study was conducted in 14 subjects, and PK parameters for ALA and PpIX were determined. In 50% (7/14) of the subjects, the baseline-corrected PpIX concentration was negative in at least 50% of the samples, so the AUC could not be reliably estimated. The baseline-corrected mean ± standard deviation of Cmax for ALA and PpIX were 95.6 ± 120.6 ng/mL and 0.95 ± 0.71 ng/mL, respectively. The median time to peak concentration (Tmax) for ALA and PpIX was 2 hours and 12 hours after administration, respectively. The mean AUCt for ALA was 261.1 ± 229.3 ng·hr/mL. The mean half-life (t1/2) for ALA was 8.5 ± 6.7 hours. In 12 healthy subjects, the absolute bioavailability of ALA after administration of the recommended dose of ALA solution was 100.0% ± 1.1, ranging from 78.5% to 131.2%. The median time to peak plasma concentration of ALA was 0.8 hours (range 0.5–1.0 hours). In 12 healthy subjects, the urinary excretion rate of maternal aminolevulinic acid (ALA) within 12 hours after administration of the recommended dose of ALA solution was 34 ± 8% (mean ± standard deviation), ranging from 27% to 57%.
In healthy volunteers, the volume of distribution of aminolevulinic acid was 9.3 ± 2.8 L for intravenous administration and 14.5 ± 2.5 L for oral administration. [11961050]

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Metabolism/Metabolite>
Exogenous aminolevulinic acid (ALA) is metabolized to PpIX, but the proportion of ALA metabolized to PpIX is unknown. The mean plasma AUC of PpIX is less than 6% of that of ALA.
After local administration, PpIX is synthesized in situ within the skin.
Half-life: The mean half-life after oral administration was 0.70 ± 0.18 h, and the mean half-life after intravenous administration was 0.83 ± 0.05 h.
Biological Half-Life
The mean elimination half-life (t_1/2) of aminolevulinic acid in the topical solution formulation was 5.7 ± 3.9 hours, and the mean half-life of the oral solution formulation was 0.9 ± 1.2 hours. In another pharmacokinetic study of 6 healthy volunteers, using a 128 mg dose, the mean half-life after oral administration was 0.70 ± 0.18 hours, and the mean half-life after intravenous administration was 0.83 ± 0.05 hours.

Toxicity Summary
Based on the hypothesized mechanism of action, the photosensitivity reaction following topical application of aminolevulinic acid (ALA) solution is due to the metabolic conversion of ALA into protoporphyrin IX (PpIX), which accumulates in the skin where aminolevulinic acid is applied. When exposed to light of appropriate wavelength and energy, the accumulated PpIX undergoes a photodynamic reaction, a cytotoxic process dependent on the simultaneous presence of light and oxygen. Light absorption leads to the excited state of porphyrin molecules, followed by spin shift of PpIX towards molecular oxygen to generate singlet oxygen, which can further react to generate superoxide anions and hydroxyl radicals. The use of aminolevulinic acid for photosensitization of actinic keratosis lesions, combined with irradiation using the BLU-UTM blue light photodynamic therapy device (BLU-U), forms the basis of aminolevulinic acid photodynamic therapy (PDT).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information regarding oral administration of aminolevulinic acid during lactation. To minimize infant exposure, breastfeeding can be suspended for 24 hours after oral administration. Due to extremely low systemic absorption, breastfeeding is not expected to result in infant exposure to topically applied aminolevulinic acid. Aminolevulinic acid-induced photodynamic therapy has been successfully used to treat various nipple skin lesions. This treatment method appears to protect nipple anatomy and is beneficial for breastfeeding.
◉ Effects on breastfed infants
No relevant published information was found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date.

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Protein binding
In in vitro experiments, using aminolevulinic acid (ALA) at concentrations up to approximately 25% of the maximum plasma concentration after using ALA solution at the recommended dose, the average protein binding rate of ALA was 12%.

[1]. Effects of 5-Aminolevulinic Acid on Gene Expression, Immunity, and ATP Levels in Pacific White Shrimp, Litopenaeus vannamei. Mar Biotechnol (NY). 2018 Aug 25.

Pharmacodynamics
The metabolism of 5-aminolevulinic acid (ALA) is the first step in the biochemical pathway of heme synthesis. ALA itself is not a photosensitizer, but rather a metabolic precursor of the photosensitizer protoporphyrin IX (PpIX). ALA synthesis is typically tightly regulated by feedback inhibition of ALA synthase, an inhibition likely related to intracellular heme levels. When ALA enters the cell, it bypasses this regulatory point, leading to the accumulation of PpIX. PpIX then adds iron to its nucleus via ferrochelase, ultimately converting to heme. 1. ALA Background: 5-Aminolevulinic acid (ALA) is a key precursor in porphyrin biosynthesis, and porphyrins are involved in the synthesis of heme, chlorophyll, and vitamin B12 in organisms. According to reports, alpha-linolenic acid (ALA) can regulate the energy metabolism and antioxidant capacity of aquatic animals. This study further investigated the effects of ALA on the immune function and gene expression of Litopenaeus vannamei. [1] 2. Optimal dosage: Studies have shown that the optimal feed addition for Litopenaeus vannamei is 0.5 g/kg. At this dosage, ALA showed the most significant promoting effect on the immunity, ATP synthesis and gene expression of shrimp, while higher doses (1.0 g/kg) did not further enhance these effects, indicating that the bioactivity of ALA in shrimp is positively correlated with dosage. [1]

C5H9NO3

131.12986

131.058

C, 45.80; H, 6.92; N, 10.68; O, 36.60

106-60-5

5-Aminolevulinic acid hydrochloride;5451-09-2;5-Aminolevulinic acid-13C;123253-93-0

137

Typically exists as solid at room temperature

1.2±0.1 g/cm3

298.4±20.0 °C at 760 mmHg

156-158 °C
156 - 158 °C

134.3±21.8 °C

0.0±1.3 mmHg at 25°C

1.482

-0.93

80.39

2

4

4

9

121

0

NCC(=O)CCC(O)=O

ZGXJTSGNIOSYLO-UHFFFAOYSA-N

InChI=1S/C5H9NO3/c6-3-4(7)1-2-5(8)9/h1-3,6H2,(H,8,9)

5-amino-4-oxopentanoic acid

5-Aminolevulinic acid; Aminolevulinic acid; 106-60-5; 5-Amino-4-oxopentanoic acid; 5-Aminolevulinate; Pentanoic acid, 5-amino-4-oxo-; delta-aminolevulinic acid; Aladerm; 5451-09-2 (HCl); 106-60-5 (free); 868074-65-1 (phosphate)

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)

DMSO : ~100 mg/mL (~762.60 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (19.07 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (19.07 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (19.07 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。