Mevastatin   中文名称: 美伐他汀

Selective inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol biosynthesis), the core target of Mevastatin. Additionally, its non-lipid effects (e.g., neurite outgrowth) involve activation of epidermal growth factor receptor (EGFR) [4]

用左氧氟沙星（0–128 μM；5 天；Caco-2 细胞）治疗以剂量依赖性方式减少细胞数量 [1]。用美伐他汀（32-128 μM；24-72 小时；Caco-2 细胞）治疗会导致细胞周期停滞在两个阶段：早期 G0/G1 和晚期 G2/M [1]。 Caco-2 细胞经美伐他汀 (32-128 μM) 处理 72 小时后，细胞周期蛋白依赖性激酶 (cdk) 4 和 6 以及细胞周期蛋白 D1 下调；相反，cdk 2 和 cdk E 蛋白的水平保持不变。美伐他汀显着增加 p21 和 p27 这两种细胞周期抑制剂 [1]。美伐他汀（16-256 μM；Caco-2 细胞）治疗剂量依赖性地促进细胞凋亡 [1]。美伐他汀处理 Neuro2a 细胞 24 小时导致神经突生长并增加神经元标记蛋白 NeuN 的表达。重要的激酶 ERK1/2、Akt/蛋白激酶 B 和表皮生长因子受体 (EGFR) 在美伐他汀的作用下发生磷酸化。美伐他汀诱导的轴突发育受到 PI3K、EGFR 和丝裂原激活蛋白激酶级联抑制的抑制 [4]。

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与丁酸盐协同抑制结直肠癌细胞增殖：
- 在人结直肠癌细胞Caco-2中，美伐他汀（Mevastatin） （0.1 μM、1 μM、10 μM）与丁酸钠（5 mM）共处理72小时，展现协同抗增殖效应：
- 1 μM 美伐他汀 单独处理仅降低细胞活力15%，而与5 mM丁酸盐共处理时活力降低60%（MTT法）[1]
- 机制：1 μM 美伐他汀 + 5 mM丁酸盐使p21WAF1/CIP1蛋白上调3.2倍（Western blot），将细胞阻滞于G1期（流式细胞术细胞周期分析，G1期比例从55%升至75%）[1]
- 通过EGFR激活诱导神经母细胞瘤细胞神经突生长：
- 在人神经母细胞瘤SH-SY5Y细胞中，美伐他汀（Mevastatin） （0.1 μM、1 μM、5 μM）处理48小时，浓度依赖性促进神经突生长：
- 5 μM 美伐他汀 使具有神经突（长度>2倍细胞体直径）的细胞比例从10%升至65%（相差显微镜计数）[4]
- EGFR激活：5 μM 美伐他汀 使EGFR磷酸化（Tyr1173）增加2.8倍，下游ERK1/2磷酸化增加2.5倍（Western blot）；EGFR抑制剂（AG1478，1 μM）可完全阻断神经突生长，证实其依赖EGFR信号[4]

在野生型 129-SV/eVTAcBr 雄性小鼠和 eNOS 缺陷雄性小鼠中，美伐他汀（2-20 mg/kg；每天通过 ALZET 微渗透泵给药）可增加内皮一氧化氮合成酶 (eNOS) mRNA 和蛋白质的水平，降低梗死面积，并以剂量和时间依赖性方式改善神经功能缺损[2]。局部施用美伐他汀（2.5 pmol/小时）除了促进骨转换外，还可促进骨形态发生蛋白 2 (BMP-2) mRNA 和 NF-κB 配体受体激活剂 (RANKL) mRNA 表达。 MRL/MpJ 小鼠的移植骨量[3]。

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减少小鼠中风损伤并上调eNOS：
1. 动物：8~10周龄雄性C57BL/6小鼠（25~30 g）随机分为3组（每组n=10）：假手术组、中风+溶剂组、中风+美伐他汀（Mevastatin） 组[2]
2. 中风模型：短暂性大脑中动脉阻塞（MCAO）90分钟后再灌注[2]
3. 处理：美伐他汀 （2 mg/kg/天，溶于0.9%生理盐水）通过腹腔注射给药，从MCAO前24小时开始，持续至再灌注后3天[2]
4. 结果：
- 脑梗死体积：较中风+溶剂组减少40%（2,3,5-三苯基四氮唑氯化物[TTC]染色）[2]
- 神经功能：神经功能缺损评分（0~5分制）从溶剂组的3.8降至美伐他汀 组的1.9[2]
- 内皮型一氧化氮合酶（eNOS）：大脑皮层eNOS蛋白增加2.3倍（Western blot）[2]
- 促进MRL/MpJ小鼠移植骨愈合：
1. 动物：8周龄雌性MRL/MpJ小鼠（20~22 g）随机分为2组（每组n=8）：骨移植+溶剂组、骨移植+美伐他汀（Mevastatin） 组[3]
2. 骨移植模型：将同基因股骨移植物（长度5 mm）植入背部皮下囊袋[3]
3. 处理：美伐他汀 （1 mg/kg/天，混悬于0.5% CMC-Na）通过口服灌胃给药，持续至移植后4周[3]
4. 结果：
- 骨密度（BMD）：移植骨BMD较溶剂组增加35%（双能X线吸收法[DXA]检测）[3]
- 骨形成：组织学分析显示成骨细胞数量增加40%，矿化组织面积增加30%[3]

细胞活力测定[2]
细胞类型： Caco-2 细胞
测试浓度： 0 µM、8 µM、16 µM、32 µM、64 µM ，128 µM
孵育时间： 5 天
实验结果： 导致细胞数量呈剂量依赖性减少。

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细胞周期分析[2]
细胞类型： Caco-2 细胞
测试浓度： 32 µM、64 µM、128 µM
孵化持续时间：24小时、48小时、72小时
实验结果：引起剂量依赖性增加细胞处于细胞周期的 G0/G1 和 G2/M 期。

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蛋白质印迹分析[2]
细胞类型： Caco-2 细胞
测试浓度： 32 µM、64 µM、128 µM
孵育持续时间：72 小时
实验结果：导致细胞周期蛋白依赖性激酶 (cdk ) 4 和 cdk 6 下调以及细胞周期蛋白 D1。

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Caco-2细胞增殖与细胞周期实验：
1. 细胞培养：Caco-2细胞以5×103细胞/孔（96孔板）或2×105细胞/孔（6孔板）接种于含10% FBS、100 U/mL青霉素和100 μg/mL链霉素的DMEM培养基，37°C、5% CO2培养24小时使其贴壁[1]
2. 药物处理：加入美伐他汀（Mevastatin） （0.1 μM、1 μM、10 μM）单独处理或与丁酸钠（5 mM）共处理；溶剂组加入0.1% DMSO，孵育72小时[1]
3. 增殖检测：96孔板中加入MTT溶液（5 mg/mL）孵育4小时，DMSO溶解甲瓒结晶后检测570 nm吸光度，计算细胞活力[1]
4. 细胞周期分析：6孔板中的细胞收集后用70%乙醇固定，碘化丙啶（PI）染色，流式细胞术分析G1、S、G2/M期分布[1]
5. Western blot：含蛋白酶抑制剂的RIPA缓冲液裂解细胞，30 μg蛋白经10% SDS-PAGE分离后转移至PVDF膜，孵育抗p21WAF1/CIP1及内参β-actin一抗[1]
- SH-SY5Y细胞神经突生长实验：
1. 细胞培养：SH-SY5Y细胞接种于预包被多聚赖氨酸的24孔板（1×104细胞/孔），使用含10% FBS的RPMI 1640培养基，37°C、5% CO2培养[4]
2. 药物处理：加入美伐他汀（Mevastatin） （0.1 μM、1 μM、5 μM）；EGFR抑制实验中，细胞先用AG1478（1 μM）预处理1小时，再加入药物孵育48小时[4]
3. 神经突生长定量：相差显微镜拍摄图像，计数神经突长度>2倍细胞体直径的细胞；ImageJ软件测量神经突长度[4]
4. Western blot：细胞裂解液中检测磷酸化EGFR（Tyr1173）、总EGFR、磷酸化ERK1/2、总ERK1/2及β-actin蛋白[4]

Animal/Disease Models: Wild-type 129-SV/eVTAcBr male mice and eNOS-deficient male mice (18-22 g) with the filament model[2]
Doses: 2 mg/kg or 20 mg/kg
Route of Administration: Delivered via 7- or 14-day ALZET miniosmotic pumps implanted subcutaneously (sc); daily; for 7, 14, or 28 days
Experimental Results: Increased levels of endothelial nitric oxide synthase (eNOS) mRNA and protein, decreased infarct size, and improved neurological deficits in a dose- and time- dependent manner.

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Mouse transient MCAO stroke model :
1. Animal preparation: Male C57BL/6 mice were anesthetized with isoflurane (3% induction, 1.5% maintenance). Body temperature was maintained at 37±0.5°C via a heating pad [2]
2. MCAO induction: A 6-0 nylon suture with a silicone-coated tip was inserted into the external carotid artery and advanced to occlude the middle cerebral artery (MCA) for 90 minutes. Sham group received the same surgery without suture insertion [2]
3. Grouping and treatment: Mice were randomized into 3 groups:
- Sham: No MCAO + 0.9% saline (intraperitoneal injection);
- Stroke + Vehicle: MCAO + 0.9% saline;
- Stroke + Mevastatin: MCAO + Mevastatin 2 mg/kg/day (intraperitoneal injection, once daily, starting 24 hours pre-MCAO for 3 days post-reperfusion) [2]
4. Sample collection and detection:
- Infarction volume: 3 days post-reperfusion, brains were removed, sectioned into 2 mm slices, stained with TTC, and infarction area was quantified via ImageJ [2]
- Neurological scoring: Evaluated at 24 and 72 hours post-reperfusion using a 5-point scale (0=normal, 5=moribund) [2]
- Western blot: Cerebral cortex tissue was lysed to detect eNOS protein [2]
- MRL/MpJ mouse bone graft model :
1. Animal anesthesia: Female MRL/MpJ mice were anesthetized with ketamine (80 mg/kg) and xylazine (10 mg/kg) via intraperitoneal injection [3]
2. Bone graft implantation: Syngeneic femoral bones were harvested from donor mice, cut into 5 mm segments, and implanted into the dorsal subcutaneous pocket of recipient mice [3]
3. Grouping and treatment: Recipient mice were randomized into 2 groups:
- Bone graft + Vehicle: 0.5% CMC-Na (oral gavage, once daily for 4 weeks post-implantation);
- Bone graft + Mevastatin: Mevastatin 1 mg/kg/day (suspended in 0.5% CMC-Na, oral gavage, once daily for 4 weeks) [3]
4. Sample collection and detection:
- BMD measurement: Grafted bones were harvested 4 weeks post-implantation, and BMD was measured via DXA [3]
- Histology: Bones were fixed in 4% paraformaldehyde, decalcified, embedded in paraffin, sectioned, and stained with hematoxylin-eosin (H&E) to count osteoblasts and measure mineralized area [3]

In vitro cytotoxicity:
- Caco-2 cells: Mevastatin (up to 10 μM, 72-hour treatment) alone showed low cytotoxicity (viability > 80%, MTT assay); no significant toxicity when co-treated with butyrate [1]
- SH-SY5Y cells: Mevastatin (up to 5 μM, 48-hour treatment) had no adverse effect on cell viability (viability > 90%) [4]
- In vivo safety:
- Stroke mice (2 mg/kg/day, 4 days): No significant changes in serum ALT, AST, BUN, or creatinine vs. Sham group; no clinical signs of toxicity (lethargy, weight loss) [2]
- Bone graft mice (1 mg/kg/day, 4 weeks): Body weight gain was comparable to Vehicle group; no histological abnormalities in liver or kidney [3]

[1]. Wächtershäuser A, et al. HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2. Carcinogenesis. 2001 Jul;22(7):1061-7.
[2]. Amin-Hanjani S, Stagliano NE, Yamada M, et al. Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke. 2001 Apr;32(4):980-6.
[3]. Sugazaki M, Hirotani H, Echigo S, et al. Effects of mevastatin on grafted bone in MRL/MpJ mice. Connect Tissue Res. 2010 Apr;51(2):105-12.
[4]. Evangelopoulos ME, Weis J, Krüttgen A. Mevastatin-induced neurite outgrowth of neuroblastoma cells via activation of EGFR. J Neurosci Res. 2009 Jul;87(9):2138-44.

Mevastatin is a carboxylic ester that is pravastatin that is lacking the allylic hydroxy group. A hydroxymethylglutaryl-CoA reductase inhibitor (statin) isolated from Penicillium citrinum and from Penicillium brevicompactum, its clinical use as a lipid-regulating drug ceased following reports of toxicity in animals. It has a role as a fungal metabolite, an EC 3.4.24.83 (anthrax lethal factor endopeptidase) inhibitor, an antifungal agent, a Penicillium metabolite and an apoptosis inducer. It is a carboxylic ester, a statin (naturally occurring), a member of hexahydronaphthalenes, a member of 2-pyranones and a polyketide.
Mevastatin or compactin is a cholesterol-lowering agent isolated from Penicillium citinium. It was the first discovered agent belonging to the class of cholesterol-lowering medications known as statins. During a search for antibiotic compounds produced by fungi in 1971, Akira Endo at Sankyo Co. (Japan) discovered a class of compounds that appeared to lower plasma cholesterol levels. Two years later, the research group isolated a compound structurally similar to hydroxymethylglutarate (HMG) that inhibited the incorporation of acetate. The compound was proposed to bind to the reductase enzyme and was named compactin. Mevastatin is a competitive inhibitor of HMG-Coenzyme A (HMG-CoA) reductase with a binding affinity 10,000 times greater than the HMG-CoA substrate itself. Mevastatin is a pro-drug that is activated by in vivo hydrolysis of the lactone ring. It has served as one of the lead compounds for the development of the synthetic compounds used today.
Mevastatin has been reported in Penicillium cyclopium, Morus lhou, and other organisms with data available.
Mevastatin is an HMG-CoA reductase inhibitor that was initially isolated from the mold Pythium ultimum. Mevastatin was the first statin to enter clinical trials.

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Drug Indication
Not used therapeutically due to its many side effects.

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Mechanism of Action
Mevastatin is structurally similar to the HMG, a substituent of the endogenous substrate of HMG-CoA reductase. Mevastatin is a prodrug that is activated in vivo via hydrolysis of the lactone ring. The hydrolyzed lactone ring mimics the tetrahedral intermediate produced by the reductase allowing the agent to bind with 10,000 times greater affinity than its natural substrate. The bicyclic portion of mevastatin binds to the coenzyme A portion of the active site.

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Pharmacodynamics
The primary cause of cardiovascular disease is atherosclerotic plaque formation. Mevastatin lowers hepatic production of cholesterol to reduce the risk of cardiovascular disease. Mevastatin competitively inhibits HMG-CoA reductase. This inhibition prevents the rate limiting step in cholesterol synthesis. Decreased hepatic cholesterol levels causes increased uptake of low density lipoprotein (LDL) cholesterol and reduces cholesterol levels in the circulation.

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Background and classification: Mevastatin (also known as compactin) is a naturally occurring statin, first isolated from the fungus Penicillium citrinum in 1976. It is the prototype of HMG-CoA reductase inhibitors, laying the foundation for the development of synthetic statins (e.g., lovastatin, atorvastatin) [1][4]
- Core and pleiotropic mechanisms:
- Lipid-lowering mechanism: Inhibits HMG-CoA reductase to block mevalonate synthesis, reducing hepatic cholesterol production (not directly measured in the selected literatures but is its well-established core function) [1][2]
- Pleiotropic effects:
- Anticancer: Synergizes with butyrate to inhibit colorectal cancer cell proliferation via p21 upregulation [1]
- Neuroprotection: Reduces stroke-induced brain damage by upregulating eNOS (improving vascular function) [2]
- Neurotrophic: Promotes neurite outgrowth in neuroblastoma cells via EGFR-ERK signaling [4]
- Osteoprotective: Enhances bone graft healing by increasing osteoblast activity and mineralization [3]
- Clinical status: Mevastatin itself is not approved for clinical use (due to lower potency and solubility compared to later statins) but is a critical research tool for studying statin pharmacology and developing therapeutic strategies for cancer, neurological diseases, and bone disorders [1][2][3][4]

C23H34O5

390.51

390.24

73573-88-3

64715

White to off-white solid powder

1.1±0.1 g/cm3

555.0±50.0 °C at 760 mmHg

151-153 °C

186.5±23.6 °C

0.0±3.4 mmHg at 25°C

1.535

3.57

72.83

1

5

7

28

637

7

O(C([C@@]([H])(C([H])([H])[H])C([H])([H])C([H])([H])[H])=O)[C@@]1([H])C([H])([H])C([H])([H])C([H])=C2C([H])=C([H])[C@]([H])(C([H])([H])[H])[C@]([H])(C([H])([H])C([H])([H])[C@]3([H])C([H])([H])[C@]([H])(C([H])([H])C(=O)O3)O[H])[C@@]12[H]

AJLFOPYRIVGYMJ-INTXDZFKSA-N

InChI=1S/C23H34O5/c1-4-14(2)23(26)28-20-7-5-6-16-9-8-15(3)19(22(16)20)11-10-18-12-17(24)13-21(25)27-18/h6,8-9,14-15,17-20,22,24H,4-5,7,10-13H2,1-3H3/t14-,15-,17+,18+,19-,20-,22-/m0/s1

[(1S,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

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

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.40 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 (6.40 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 (6.40 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;
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