Peroxisome Proliferator-Activated Receptor γ (PPARγ) (EC50 = 0.2 μM for PPARγ transcriptional activation) [1]

Troglitazone 是一种 PPARγ 激动剂；其对人和鼠 PPARγ 受体的 EC50 值分别为 550 nM 和 780 nM[1]。曲格列酮 (2-200 μM) 对胰腺癌细胞系（MIA Paca2 和 PANC-1 细胞）具有细胞毒性，IC50 分别为 49.9 ± 1.2 和 51.3 ± 5.3 μM。在 MIA Paca2 和 PANC-1 细胞中，曲格列酮 (50 μM) 会增加染色质浓缩，增加 caspase-3 活性，并降低 Bcl-2 表达 [2]。在人肺腺癌细胞中，曲格列酮（0、1、2 和 4 μM）使 TRAIL 介导的细胞凋亡变得敏感。自噬抑制可防止曲格列酮增强 TRAIL 诱导的细胞凋亡。此外，A549 细胞中 PPARγ 的激活会诱导曲格列酮的作用[3]。

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Troglitazone（0.1-10 μM）剂量依赖性激活转染PPRE-荧光素酶报告质粒的HeLa细胞中PPARγ转录活性，1 μM浓度下荧光素酶活性增加3.5倍 [1]
- Troglitazone（5-20 μM）抑制胰腺癌细胞（PANC-1、MIA PaCa-2）增殖，72小时后GI50值分别为12 μM和15 μM；5 μM浓度使PANC-1细胞克隆形成率降低60% [2]
- Troglitazone（10 μM）预处理A549和H1299肺癌细胞24小时，增强TRAIL诱导的凋亡，凋亡率从（TRAIL单药组）18%升至（TRAIL + Troglitazone组）45%；同时促进自噬流（LC3-II/LC3-I比值增加2.8倍，p62表达降低55%）[3]
- Troglitazone（5-15 μM）上调A549细胞中PPARγ下游靶基因（aP2、AdipoQ）及死亡受体DR4/DR5表达（分别增加2.2倍和1.8倍），RT-PCR和Western blot检测证实 [3]
- 小干扰RNA（siRNA）沉默PPARγ后，Troglitazone与TRAIL在肺癌细胞中的协同凋亡效应消失 [3]

MIA Paca2 异种移植模型对曲格列酮（200 mg/kg，口服）表现出生长抑制作用[2]。

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荷PANC-1胰腺癌异种移植瘤的裸鼠（BALB/c-nu）接受Troglitazone（50、100 mg/kg，灌胃，每日1次，连续21天）处理。100 mg/kg组肿瘤体积减少58%，肿瘤重量降低52%，肿瘤组织中增殖标志物Ki-67表达下调40% [2]
- 糖尿病预防计划（临床研究）中，高危人群（糖耐量异常）口服Troglitazone（400 mg/天，中位治疗3年），2型糖尿病发病率降低54% [4]
- Troglitazone（100 mg/kg，灌胃）使PANC-1异种移植瘤组织中PPARγ蛋白表达增加，促炎细胞因子（TNF-α、IL-6）水平分别降低35%和40% [2]

PPARγ激活荧光素酶报告基因实验：HeLa细胞共转染PPARγ表达质粒、PPRE-荧光素酶报告质粒及β-肌动蛋白-海肾荧光素酶内参质粒。24小时后，用Troglitazone（0.01-10 μM）处理细胞24小时。双荧光素酶检测系统测定荧光素酶活性，计算PPARγ转录激活的EC50值 [1]
- PPARγ配体结合实验：重组人PPARγ配体结合域（LBD）与[3H]标记的PPARγ激动剂及不同浓度Troglitazone（0.05-5 μM）在4°C孵育16小时。凝胶过滤法分离结合态与游离态配体，量化放射性强度以评估结合亲和力 [1]

胰腺癌细胞增殖实验：PANC-1和MIA PaCa-2细胞在添加胎牛血清的DMEM培养基中培养，接种于96孔板，用Troglitazone（5-20 μM）处理72小时。MTT法检测细胞活力；克隆形成实验中，每孔接种200个细胞，Troglitazone（5 μM）处理14天，甲醇固定，结晶紫染色，计数克隆数 [2]
- 肺癌细胞凋亡与自噬实验：A549细胞在RPMI 1640培养基中培养，Troglitazone（5-15 μM）预处理24小时后，用TRAIL（10 ng/mL）处理48小时。Annexin V-FITC/PI双染色结合流式细胞术检测凋亡；Western blot分析LC3-I/LC3-II、p62、DR4/DR5及PPARγ表达 [3]
- 自噬流实验：转染mRFP-GFP-LC3质粒的A549细胞用Troglitazone（10 μM）处理24小时。共聚焦显微镜采集荧光图像，计数黄色斑点（自噬体）和红色斑点（自噬溶酶体）[3]
- PPARγ靶基因表达实验：Troglitazone（10 μM）处理A549细胞24小时后，提取总RNA并合成cDNA。RT-PCR定量aP2、AdipoQ、DR4、DR5 mRNA水平，GAPDH作为内参 [3]

Absorption, Distribution and Excretion
Absorbed rapidly. Food increases the extent of absorption by 30% to 85%.

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Metabolism / Metabolites
A sulfate conjugate metabolite (Metabolite 1) and a quinone metabolite (Metabolite 3) have been detected in the plasma of healthy males. A glucuronide conjugate (Metabolite 2) has been detected in the urine and also in negligible amounts in the plasma. In healthy volunteers and in patients with type 2 diabetes, the steady-state concentration of Metabolite 1 is six to seven times that of troglitazone and Metabolite 3. In in vivo drug interaction studies, troglitazone has been shown to induce cytochrome P450 CYP3A4 at clinically relevant doses.
Troglitazone has known human metabolites that include (2S,3S,4S,5R)-6-[[2-[[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]methyl]-2,5,7,8-tetramethyl-3,4-dihydrochromen-6-yl]oxy]-3,4,5-trihydroxyoxane-2-carboxylic acid.
A sulfate conjugate metabolite (Metabolite 1) and a quinone metabolite (Metabolite 3) have been detected in the plasma of healthy males. A glucuronide conjugate (Metabolite 2) has been detected in the urine and also in negligible amounts in the plasma. In healthy volunteers and in patients with type 2 diabetes, the steady-state concentration of Metabolite 1 is six to seven times that of troglitazone and Metabolite 3. In in vivo drug interaction studies, troglitazone has been shown to induce cytochrome P450 CYP3A4 at clinically relevant doses.
Half Life: 16-34 hours

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Biological Half-Life
16-34 hours

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Oral bioavailability of Troglitazone in rats was 32% after a single 10 mg/kg dose [1]
- Plasma protein binding rate of Troglitazone was >99% in human plasma and 98% in rat plasma [1]
- The terminal elimination half-life (t1/2) was 4.5 hours after intravenous injection and 6.8 hours after oral administration in rats [1]
- Troglitazone was primarily metabolized in the liver via cytochrome P450 3A4 (CYP3A4)-mediated oxidation, forming sulfate conjugates. Approximately 70% of the dose was excreted in feces and 25% in urine (as metabolites) within 72 hours [1]
- The drug distributed widely to tissues, with highest concentrations in adipose tissue, liver, and kidney in rats [1]

Toxicity Summary
Troglitazone is a thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin. It has a unique mechanism of action that is dependent on the presence of insulin for activity. Troglitazone decreases hepatic glucose output and increases insulin dependent glucose disposal in skeletal muscle. Its mechanism of action is thought to involve binding to nuclear receptors (PPAR) that regulate the transcription of a number of insulin responsive genes critical for the control of glucose and lipid metabolism. Troglitazone is a ligand to both PPAR‘± and PPAR‘_, with a highter affinity for PPAR‘_. The drug also contains an ‘±-tocopheroyl moiety, potentially giving it vitamin E-like activity. Troglitazone has been shown to reduce inflammation, and is associated with a decrase in nuclear factor kappa-B (NF-‘_B) and a concomitant increase in its inhibitor (I‘_B). NF-‘_B is an important cellular transcription regulator for the immune response. Unlike sulfonylureas, troglitazone is not an insulin secretagogue.

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Hepatotoxicity
Large prospective studies showed that significant elevations in serum aminotransferase levels (equal to or greater than 3 times the upper limit of the normal range [ULN]) occurred in 1.9% of patients with diabetes treated with troglitazone for 24 to 48 weeks, compared to only 0.6% in placebo recipients. These enzyme elevations were usually asymptomatic and often resolved despite continuation of therapy. Nevertheless, elevations >10 times ULN occurred in 0.5% of patients (but in no placebo recipient) and a proportion of these developed symptoms of liver injury and jaundice. Soon after the approval of troglitazone as therapy for type 2 diabetes in the United States, cases of severe acute liver injury began to be reported, and dramatic case reports as well as small case series documented that clinically significant injury was occurring in 1:1000 to 1:10,000 recipients. The latency to onset of injury was typically 1 to 6 months and the onset was marked by fatigue, weakness, dark urine and jaundice, and an acute hepatitis-like elevation in serum enzymes (hepatocellular pattern). Allergic phenomena (rash, fever, eosinophilia) were uncommon and serum autoantibodies were not usually present. Liver biopsies showed acute inflammatory changes and variable degrees of necrosis, ranging from rare spotty necrosis to bridging hepatic necrosis and submassive or massive necrosis. At least two dozen cases of acute liver failure and death or need for liver transplantation were reported to the FDA before troglitazone was withdrawn from use in 2000.
Likelihood score: A (well recognized cause of clinically apparent liver injury).

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Protein Binding
> 99% (primarily to serum albumin)

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Hepatotoxicity: Rats treated with Troglitazone (100 mg/kg/day, po for 28 days) showed 2.5-fold increases in serum ALT and AST levels, along with hepatocellular vacuolation [1]
- Clinical hepatotoxicity: In the Diabetes Prevention Program, 0.5% of participants treated with Troglitazone (400 mg/day) developed severe liver injury, leading to the drug’s withdrawal from the market [4]
- Acute toxicity in mice: Oral LD50 was 1800 mg/kg; no treatment-related death was observed at doses ≤1000 mg/kg [1]
- Troglitazone (≤20 μM) showed no significant cytotoxicity to normal human hepatocytes (HL-7702), with cell viability >85% after 72 hours of treatment [2]

[1]. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000 Feb 24;43(4):527-50.

[2]. In vitro and in vivo cytotoxicity of troglitazone in pancreatic cancer. J Exp Clin Cancer Res. 2017 Jul 3;36(1):91.

[3]. PPARγ activation by troglitazone enhances human lung cancer cells to TRAIL-induced apoptosis via autophagy flux. Oncotarget. 2017 Apr 18;8(16):26819-26831.

[4]. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes. 2005 Apr;54(4):1150-6.

Troglitazone is a member of chromanes and a thiazolidinone. It has a role as a hypoglycemic agent, an antioxidant, a vasodilator agent, an anticonvulsant, an anticoagulant, a platelet aggregation inhibitor, an antineoplastic agent, an EC 6.2.1.3 (long-chain-fatty-acid--CoA ligase) inhibitor and a ferroptosis inhibitor.
Troglitazone was withdrawn in 2000 due to risk of hepatotoxicity. It was superseded by [pioglitazone] and [rosiglitazone].
Troglitazone was the first thiazolidinedione approved for use in the United States and was licensed for use in type 2 diabetes in 1997, but withdrawn 3 years later because of the frequency of liver injury including acute liver failure associated with its use.
Troglitazone is an orally-active thiazolidinedione with antidiabetic and hepatotoxic properties and potential antineoplastic activity. Troglitazone activates peroxisome proliferator-activated receptor gamma (PPAR-gamma), a ligand-activated transcription factor, thereby inducing cell differentiation and inhibiting cell growth and angiogenesis. This agent also modulates the transcription of insulin-responsive genes, inhibits macrophage and monocyte activation, and stimulates adipocyte differentiation. (NCI04)
Troglitazone was withdrawn in 2000 due to risk of hepatotoxicity. It was superseded by pioglitazone and rosiglitazone.
A chroman and thiazolidinedione derivative that acts as a PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPAR) agonist. It was formerly used in the treatment of TYPE 2 DIABETES MELLITUS, but has been withdrawn due to hepatotoxicity.

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Drug Indication
For the treatment of Type II diabetes mellitus. It is used alone or in combination with a sulfonylurea, metformin, or insulin as an adjunct to diet and exercise.
FDA Label

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Mechanism of Action
Troglitazone is a thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin. It has a unique mechanism of action that is dependent on the presence of insulin for activity. Troglitazone decreases hepatic glucose output and increases insulin dependent glucose disposal in skeletal muscle. Its mechanism of action is thought to involve binding to nuclear receptors (PPAR) that regulate the transcription of a number of insulin responsive genes critical for the control of glucose and lipid metabolism. Troglitazone is a ligand to both PPARα and PPARγ, with a highter affinity for PPARγ. The drug also contains an α-tocopheroyl moiety, potentially giving it vitamin E-like activity. Troglitazone has been shown to reduce inflammation, and is associated with a decrase in nuclear factor kappa-B (NF-κB) and a concomitant increase in its inhibitor (IκB). Unlike sulfonylureas, troglitazone is not an insulin secretagogue.

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Pharmacodynamics
Troglitazone is an oral antihyperglycemic agent which acts primarily by decreasing insulin resistance. Troglitazone is used in the management of type II diabetes (noninsulin-dependent diabetes mellitus (NIDDM) also known as adult-onset diabetes). It improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Troglitazone is not chemically or functionally related to either the sulfonylureas, the biguanides, or the g-glucosidase inhibitors. Troglitazone may be used concomitantly with a sulfonylurea or insulin to improve glycemic control.

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Troglitazone is a selective agonist of PPARγ, a nuclear receptor involved in regulating glucose metabolism, lipid homeostasis, inflammation, and cell proliferation [1]
- Its anti-tumor mechanism involves PPARγ activation, which inhibits tumor cell proliferation, induces apoptosis, enhances TRAIL sensitivity via autophagic flux activation and DR4/DR5 upregulation, and suppresses tumor angiogenesis [2][3]
- Troglitazone was previously approved for the treatment of type 2 diabetes mellitus to improve insulin resistance, but was withdrawn globally in 2000 due to severe hepatotoxicity [4]
- The drug exhibits anti-inflammatory activity by reducing pro-inflammatory cytokine (TNF-α, IL-6) production and inhibiting NF-κB signaling pathway [2]
- Troglitazone serves as a research tool to study PPARγ-mediated signaling in metabolic diseases and cancer [1][2]
[3]

C24H27NO5S

441.54

441.16

97322-87-7

Troglitazone-d4;2749370-85-0

5591

White to off-white solid powder

1.3±0.1 g/cm3

657.0±55.0 °C at 760 mmHg

184-186°C

351.2±31.5 °C

0.0±2.1 mmHg at 25°C

1.608

4.99

110.16

2

6

5

31

681

0

GXPHKUHSUJUWKP-UHFFFAOYSA-N

InChI=1S/C24H27NO5S/c1-13-14(2)21-18(15(3)20(13)26)9-10-24(4,30-21)12-29-17-7-5-16(6-8-17)11-19-22(27)25-23(28)31-19/h5-8,19,26H,9-12H2,1-4H3,(H,25,27,28)

5-[[4-[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromen-2-yl)methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.66 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: ≥ 2.08 mg/mL (4.71 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 20.8 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: ≥ 2.08 mg/mL (4.71 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 20.8 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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配方 4 中的溶解度: 10 mg/mL (22.65 mM) in 0.5% CMC-Na 0.5% Tween-80 (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。

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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。