Endogenous Metabolite; PPARβ/δ (Kd = 17 nM); PPARα (Kd = 103 nM); PPARγ (Kd = 178 nM); PPARα (IC50 = 14 nM); PPARγ (IC50 = 14 nM); RARβ (IC50 = 14 nM)

视黄酸/retinoic acid，也称为全反式视黄酸，或 ATRA，是维生素 A 的高效衍生物，几乎是所有重要的生理过程和功能所必需的。它在 530 多个不同基因的转录控制中发挥作用。视黄酸的作用机制是通过其作为核视黄酸受体 (RARα-γ) 的激活配体的作用，与视黄酸 X 受体 (RXRα-γ) 结合形成异二聚体[1]。视黄酸 (RA) 的 Kd 值在 100 至 200 nM 之间，以低亲和力与 PPARα 和 PPARγ 结合。另一方面，视黄酸与 PPARβ/δ 结合时表现出高亲和力和同种型选择性，Kd 为 17 nM [2]。视黄酸 (RA) 受体 RARα、RARβ、RARγ 和 PPARβ/δ 以及视黄酸结合蛋白 CRABP-II 和 FABP5 由未分化的 P19 细胞表达。用视黄酸处理细胞诱导分化导致 CRABP-II 短暂过度表达和 FABP5 下调，这在相关蛋白质和 mRNA 水平上检测到。经过最初的下降后，成熟神经元中的 FABP5 蛋白和 mRNA 水平与未分化的 P19 细胞相比上升了 2-2.5 倍。 PPARβ/δ和RARα的水平没有受到分化诱导的显着影响。到第 4 天，RARγ mRNA 水平下降了近 5 倍，并且在成熟神经元中保持较低水平 [3]。视黄酸 (RA) 是由视黄醇（维生素 A）产生的一种形态发生素，在细胞发育、分化和器官发生中发挥着至关重要的作用。视黄酸与视黄酸受体 (RAR) 和视黄酸 X 受体 (RXR) 相互作用，调节靶基因的表达 [4]。

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UAB30是一种RXR选择性激动剂，已被证明具有潜在的癌症化学预防特性。由于其疗效高、毒性低，目前正由国家癌症研究所在人体I期临床试验中进行评估。虽然UAB30显示出作为低毒化学预防药物的前景，但其作用机制尚不清楚。在这项研究中，我们研究了UAB30对人类器官型皮筏培养物和小鼠表皮基因表达的影响。这项研究的结果表明，用UAB30治疗会导致负责全反式视黄醇摄取和代谢为全反式-视黄酸/retinoic acid（ATRA）的基因上调，ATRA是RAR核受体的天然激动剂。与这些基因表达的增加一致，ATRA在人类皮肤筏中的稳态水平升高。在紫外线B（UVB）照射的小鼠皮肤中，发现ATRA靶基因的表达减少。在UVB诱导的鳞状细胞癌和基底细胞癌小鼠模型的表皮中也观察到ATRA敏感基因的表达减少。然而，在UVB照射前用UAB30治疗小鼠皮肤可以防止UVB诱导的一些ATRA反应基因表达的降低。考虑到UAB30对表皮中的ATRA信号的积极作用及其低毒性，它可以作为一种化学预防剂用于治疗非毛细胞瘤皮肤癌症，特别是在器官移植受者和其他高危人群中。[1]

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维甲酸/retinoic acid（RA）调节许多靶基因的转录，从而调节无数的生物过程。众所周知，RA通过激活视黄酸受体（RAR）发挥作用，RAR反过来控制细胞分化、增殖和凋亡。然而，已经发表了关于RA各种不同且有时相反的行为的令人困惑的报道。因此，虽然RA在某些情况下诱导细胞凋亡并抑制细胞生长，但在其他情况下，它会增强增殖并充当抗凋亡剂。这些观察结果提出了除RAR之外的信号通路可能参与调节RA活动的可能性。在这里，我们表明RA是另一种核受体的高亲和力配体，即孤儿受体过氧化物酶体增殖物激活受体（PPAR）β/δ。我们证明，虽然RA不激活PPARα和PPARγ，但它以纳摩尔亲和力与PPARβ/δ结合，调节受体的构象，促进与辅激活子SRC-1的相互作用，并有效激活PPARβ/δ介导的转录。因此，RA的转录信号传导是通过双重途径发挥的，为理解对这种激素的不同细胞反应提供了理论基础。[2]

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维甲酸/retinoic acid（RA）通过激活核受体维甲酸受体（RAR）和过氧化物酶体增殖物激活受体（PPAR）β/δ及其各自的同源脂质结合蛋白CRABP-II和FABP5来调节基因转录。RA诱导神经元分化，但激素的两种转录途径对这一过程的贡献尚不清楚。在这里，我们表明RA诱导的P19干细胞向神经元祖细胞的承诺是由CRABP-II/RAR通路介导的，FABP5/PPARβ/δ通路可以通过诱导RAR阻遏物SIRT1和Ajuba来抑制这一过程。与神经发生早期阶段的抑制活性相反，FABP5/PPARβ/δ通路促进神经元祖细胞向成熟神经元的分化，这一活性部分由PPARβ／δ靶基因PDK1介导。因此，RA诱导的神经元分化在早期通过RAR介导，在晚期通过PPARβ/δ介导。RA信号传导的转换是通过RARβ的瞬时上调来实现的，同时伴随着分化早期CRABP-II/FABP5比值的瞬时增加。根据这些结论，与野生型动物相比，FABP5缺失小鼠的海马体显示出神经元祖细胞的过度积累和成熟神经元的缺陷。[3]

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视黄酸（RA）是一种来源于视黄醇（维生素a）的形态发生因子，在细胞生长、分化和器官发生中起着重要作用。从视黄醇生产RA需要两组不同脱氢酶催化的连续酶促反应。视黄醇首先被氧化成视网膜，然后被氧化成RA。RA与视黄酸受体（RAR）和视黄酸X受体（RXR）相互作用，然后调节靶基因表达。在这篇综述中，我们讨论了RA的代谢和RA信号通路的重要组成部分，并强调了目前对RA在早期胚胎发育中功能的理解。[4]

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维甲酸/retinoic acid（RA）通过激活RA受体（RAR）这一转录因子家族，对细胞生长和分化产生多效作用。这些受体存在三种亚型，RARα、RARβ和RARγ。受体在不同的细胞类型和发育阶段有不同的表达，这表明它们可能调节不同的基因集。我们已经鉴定出一种具有选择性RARα拮抗剂特征的合成维甲酸。这种拮抗剂可以抵消RA对HL-60细胞分化和B淋巴细胞多克隆活化的影响。除了其潜在的实际相关性外，这种和其他特定的拮抗剂将有助于剖析RAR系统，并将许多RA调节的功能分配给一个给定的受体。[5]

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异硫氰酸盐和酚类抗氧化剂可以通过激活Nrf2（NF-E2 p45-相关因子2）来预防癌症，Nrf2是一种通过抗氧化反应元件（ARE）增强子控制细胞保护基因表达的转录因子。使用人乳腺MCF7-衍生的AREc32报告细胞系，我们现在报告全反式视黄酸（ATRA）和其他视黄酸受体α（RARAalpha）激动剂显著降低Nrf2介导癌症化学预防剂诱导ARE驱动基因的能力，所述化学预防剂包括丁基羟基茴香醚的代谢产物，叔丁基氢醌（tBHQ）。在AREc32细胞中，由Nrf2调节的醛酮还原酶（AKR）AKR1C1和AKR1C2基因的基础和tBHQ诱导表达也受到ATRA的抑制。RARalpha的拮抗剂增强了tBHQ对ARE驱动基因表达的诱导，使用RNAi敲除RARalpha也是如此[6]。

将浓度为 0.3 μM 的视黄酸 (GMP) 应用于浸入含视黄酸的鱼缸水中的胚胎后，斑马鱼在 24 和 48 小时后表现出更快的视杆细胞分化[6]。

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RA抑制小鼠小肠中ARE基因库的表达。[6]
为了研究视黄酸/RA是否在体内抑制ARE调节基因的表达，将Nrf2-/-和Nrf2+/+小鼠置于维生素a缺乏（VAD）饮食中。已知通过Nrf2调节的蛋白质的蛋白质印迹显示，VAD饮食的WT小鼠小肠中Gstm5、GCLC、NQO1和Gsta1/2的水平显著增加（图6）。在VAD饮食的Nrf2−/-小鼠中，这些蛋白质的水平没有增加。对VAD饮食的WT小鼠施用维甲酸/ATRA（10mg/kg，2周腹腔注射）几乎完全阻断了小肠中Gstm5、GCLC、NQO1和Gsta1/2蛋白的增加（图6，泳道5），表明维甲酸在体内抑制Nrf2功能。对对照饮食的WT小鼠施用ATRA不影响Gstm5、GCLC、NQO1或Gsta1/2的表达（数据未显示）。

荧光滴定法[2]
细菌表达的mPPARα-LBD、mPPARβ/δ-LBD和mPPARγ-LBD（0.2-1μm）直接在试管中用溶于乙醇的视黄酸/RA滴定。乙醇浓度通常低于1%，从不超过2%。为了确保蛋白质和配体之间的平衡，监测荧光，直到达到恒定值。通过跟踪伴随RA结合的蛋白质固有荧光（激发，280 nm；发射，340 nm）的降低来监测滴定的进展。配体的内部过滤，由蛋白质饱和后观察到的线性斜率反映，如所述进行了校正。对校正后的数据进行分析，以获得平衡离解常数（Kd）。通过将数据拟合到从简单结合理论导出的方程（1）中进行分析， （方程式1） 其中F是观察到的荧光，F 0和F∞分别是无配体和饱和时的荧光，P T和R T分别是蛋白质和RA/视黄酸的总浓度，Ka是缔合常数（Ka=1/Kd）。

皮肤Raft中维甲酸/ATRA的检测[1]
将UAB30在DMSO（50 mM）中的浓缩溶液的等分试样加入培养基中，使最终浓度达到2μM。每隔一天更换一次培养基，并补充新鲜的UAB30。对照样品的培养基仅补充DMSO。收获后，将筏培养物的表皮从下面的胶原蛋白床上剥离。将UAB30处理或DMSO处理的培养物合并到三个样品中，每个样品包含五个筏，并基本上按照[52]中所述提取维甲酸。在黑暗中，将每个样品在0.5mL冰冷的磷酸盐缓冲盐水（PBS）中均质化，转移到硅化玻璃管中，并与0.5mL含有0.025M氢氧化钾的乙醇混合。用2mL己烷提取非极性维甲酸，在氮气流下干燥有机相，在50μL己烷：乙腈（70:30）中复溶，并如前所述通过反相HPLC进行分析。通过加入45μL 4M盐酸酸化剩余的水相，并用另外2mL己烷提取极性维甲酸（包括ATRA和UAB30）。将提取物干燥并在400μL乙腈中复溶。

组织样本中视黄酸/ATRA的LC-MS-MS分析基本上如前所述进行，但有一些修改。为了量化干燥提取物中存在的ATRA或UAB30的浓度，将50-μL等分试样注入岛津LC-10AD HPLC（包括脱气器），该HPLC与Applied Biosystems 4000 Q Trap质谱仪连接。用于所有分析的柱是SUPELCOSIL ABZ PLUS（10 cm x 2.1 mm，3μm）。使用梯度程序将含有40%乙腈、30%甲醇和30%超纯水的流动相A与含有55%乙腈、30%甲烷和15%超纯水的移动相B混合。每个流动相含有0.01%v/v的甲酸。用于混合流动相的梯度程序为：0至5分钟，100%A至100%B；5至19分钟，100%B；19至20分钟，100%B至100%A；20至30分钟，100%A.流动相的流速保持恒定在200μL/min。质谱仪在Analyst 1.4.2软件控制的多反应监测中使用大气压化学电离（APCI）源运行。ATRA和UAB30的停留时间为40ms。最佳阳性APCI检测条件为：幕气10、喷雾器气3、碰撞气6、离子源70和温度350°C。

每个样品注射三次，三次注射的平均值用于估算其视黄酸/ATRA或UAB30浓度。对于ATRA，四极杆1（Q1）中选择了301 m/z，四极杆3（Q3）中定量了123 m/z的离子碎片离子。对于UAB30，第一季度选择295 m/z，第三季度选择165 m/z。在分析之前，使用Analyst中的优化子程序对每个峰的去簇潜力、入口潜力、碰撞能量和碰撞单元出口潜力进行了优化。

为了定量ATRA水平，使用每种浓度3次注射的0.0-1.6 pmol/50μL视黄酸/ATRA注射液（7种浓度，变化2倍）进行校准曲线。将123m/z峰的总离子电流面积（TIC）拟合为线性方程，以建立校准曲线。将123m/z峰的TIC面积测量三次并取平均值。使用平均峰面积和线性校准曲线测定样品中ATRA的内源性浓度。除了校准曲线和定量使用165 m/z片段峰，以及在构建校准曲线时使用不同浓度范围（0.0-1.0 pmol/50μL UAB30注射液）外，UAB30使用了相同的方法。

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Transient Transfection。[6]
使用Lipofectamine 2000试剂（Life Technologies）在70-80%融合率下用Nrf2表达载体转染AREc32细胞。转染后5小时，在有或没有1μM维甲酸/ATRA的情况下，用含有10μM tBHQ的新鲜DMEM替换培养基。对于对照实验，向培养基中加入模拟转染（无质粒DNA）和单独的载体（0.1%体积/体积DMSO）。在收获和分析细胞之前，将细胞放置24小时以对外源性物质产生反应。在对照实验中，将不含DNA的转染试剂单独加入细胞中，用DMSO处理2小时。
对于AREc32细胞中的RAR敲除实验，从Ambion购买了靶向RARαmRNA不同区域的两个预连接siRNA序列1（5′-GGAAUUGUGCUGUUAUUtt-3′）和2（5′GCUCACAUCAUCUCAUCATT-3′）。类似地，使用特异性靶向人RARγ的预先验证的siRNA（5′-GGAAGUGUGCGAAAUGACtt-′）转染AREc32细胞。在这些情况下，siRNA（每孔200 pmol）和Lipofectamine 2000试剂（每孔10μl）在六孔板中用1 ml Optimum稀释，并在20°C下孵育20分钟。此后，4×105个细胞在4 ml不含抗生素的生长培养基中稀释，并直接分配到每个孔中。孵育24小时后，用10μM tBHQ、1μM视黄酸/ATRA或10μM tBHQ加1μM ATRA在新鲜DMEM中处理细胞24小时。

Homozygous Nrf2 KO mice were used. Two-month-old C57BL/6 Nrf2−/− and Nrf2+/+ male mice were used in this study. All animal procedures were carried out under a United Kingdom Home Office license and with local ethical approval. Nrf2−/− and Nrf2+/+ (n = 2–3) mice were placed on a VAD (Special Diet Service) or control diet for 6 weeks and then killed. Nrf2+/+ mice were also placed on a VAD diet for 6 weeks; during the last two weeks, they received either no treatment, retinoic acid/ATRA i.p. daily at 10 mg/kg, or the equivalent volume of corn oil. Mice were killed and the small intestine excised, washed, and frozen in liquid nitrogen. [6]

Absorption, Distribution and Excretion
Topical application of retinoic acid is expected to remain in the stratum corneum with minimal systemic absorption. One study showed that the total transdermal absorption rate of topically applied radiolabeled retinoic acid was 2% after 28 days. This study also examined the absorption of a once-daily combination of 1.9 g retinoic acid and benzoyl peroxide for 14 days. At steady state on day 14, the mean Cmax of retinoic acid was 0.15–0.19 ng/mL, while the mean Cmax of its metabolites, 4-keto-13-cis-retinoic acid and 13-cis-retinoic acid, was 0.27–0.34 ng/mL and 0.13–0.28 ng/mL, respectively. Cmax values varied across age groups (children, adolescents, and adults). The corresponding mean AUC0–24 ranges were 0.63–2.06, 2.39–2.89, and 0.96–1.99 ng·h/mL, respectively. The absolute bioavailability of retinoic acid after oral administration is approximately 50%. While the effect of food on retinoic acid is unclear, food increases the oral absorption of retinoids. When 22.5 mg/m² of retinoic acid was administered orally twice daily, the mean ± standard deviation (Cmax) after the first dose was 394 ± 89 ng/mL, and after one week of treatment it was 138 ± 139 ng/mL. The area under the curve (AUC) after the first dose was 537 ± 191 ng·h/mL, and after one week of treatment it was 249 ± 185 ng·h/mL. The time to peak concentration (Tmax) was 1 to 2 hours. Retinoic acid metabolites are excreted in bile and urine. Following administration of 2.75 mg and 50 mg of radiolabeled retinoic acid (0.53 and 9.6 times the approved recommended dose based on a body surface area of 1.7 m², respectively), approximately 63% of the radioactive material was recovered in urine within 72 hours, and 31% was recovered in feces within 6 days. Following oral administration, retinoic acid rapidly and extensively distributes to tissues but cannot cross the blood-brain barrier. The apparent volume of distribution (Vd) of intravenously administered retinoic acid is dose-dependent, with a significant increase at low doses. After a dose of 0.0125 mg/kg, Vd was 0.52 ± 0.12 L/kg; after a dose of 0.25 mg/kg, Vd was 0.21 ± 0.05 L/kg.
No further information available.
/Breast Milk/ It is unclear whether topically applied retinoic acid is excreted into human breast milk.
Studies with radiolabeled drugs have shown that after oral administration of 2.75 mg and 50 mg doses of retinoic acid, over 90% of the radioactive material is recovered in urine and feces. Based on data from three subjects, approximately 63% of the radioactive material was excreted in urine within 72 hours and 31% in feces within 6 days.
Following a single oral dose of 45 mg/m² (approximately 80 mg) in patients with acute promyelocytic leukemia (APL), the mean peak retinoic acid concentration was 347 ± 266 ng/mL. The time to peak concentration was 1 to 2 hours.
The apparent volume of distribution of retinoic acid has not been determined. Retinoic acid is bound to plasma at a rate exceeding 95%, primarily to albumin. Plasma protein binding remains constant across concentrations ranging from 10 to 500 ng/mL.
For more complete data on the absorption, distribution, and excretion of all-trans retinoic acids (12 in total), please visit the HSDB record page.
Metabolism/Metabolites
Retinoic acid is rapidly metabolized to form various oxidative and conjugated metabolites. It forms a variety of metabolites, including stereoisomerized derivatives (9-cis-retinoic acid or [alvitamin] and 13-cis-retinoic acid or [isoretinoic acid]), oxidized derivatives (4-hydroxyretinoic acid, 4-oxoretinoic acid, 18-hydroxyretinoic acid, 5,6-epoxyretinoic acid, 3,4-didehydroretinoic acid, and retinoic acid taurine), stereoisomerized and oxidized derivatives (13-cis-4-oxoretinoic acid), and glucuronidated derivatives (retinoyl β-glucuronide, 13-cis-retinoyl β-glucuronide, 4-oxoretinoyl β-glucuronide, 5,6-epoxyretinoic acid β-glucuronide, and 13-cis-4-oxoretinoic acid). Retinoic acid metabolites include β-glucuronide, nonpolar metabolites of retinoic acid, and retinoic acid esters. Retinoic acid is metabolized by various CYP enzymes, including CYP3A4, CYP2C8, and CYP2E. It can also be glucuroninated via UGT2B7. The metabolites 4-oxoretinoic acid and 4-oxotrans-retinoic acid glucuronide have approximately one-third the pharmacological activity of the parent compound. After one week of continuous treatment, retinoic acid induces its own metabolism when plasma concentrations drop to one-third of the initial day concentration. There is evidence that retinoic acid induces its own metabolism. In patients with acute promyelocytic leukemia (APL) receiving 45 mg/m² retinoic acid daily for 2–6 weeks, urinary excretion of 4-oxotrans-retinoic acid glucuronide increased approximately tenfold, suggesting that increased retinoic acid metabolism may be the primary mechanism leading to decreased plasma drug concentrations during continuous administration. Possible mechanisms by which continuous daily administration increases retinoic acid clearance include induction by CYP enzymes or oxidative cofactors and increased expression of cellular retinoic acid-binding proteins. Increasing the dose of retinoic acid to compensate for significant self-induction did not show an improvement in treatment response. Decreased plasma retinoic acid concentrations are associated with relapse and clinical resistance, and some researchers believe that clinical treatment failure with retinoic acid may be related to insufficient maintenance of effective drug concentrations during long-term treatment. Retinoic acid metabolites have been detected in plasma and urine. Cytochrome P450 enzymes are involved in the oxidative metabolism of retinoic acid. Metabolites include 13-cis-retinoic acid, 4-oxotrans-retinoic acid, 4-oxocis-retinoic acid, and 4-oxotrans-retinoic acid glucuronide. In patients with acute promyelocytic leukemia (APL), daily subcutaneous injection of 45 mg/m² retinoic acid for 2 to 6 weeks resulted in approximately a tenfold increase in urinary excretion of 4-oxotrans-retinoic acid glucuronide compared to baseline. Ethanol-fed rats showed enhanced microsomal retinoic acid metabolism (50%), along with increased microsomal cytochrome P450 levels (34%). Long-term ethanol intake increases liver microsomal cytochrome P450-dependent retinoic acid metabolism, which may lead to accelerated retinoic acid catabolism in the body. After intraperitoneal injection of high doses of 15-(14)C- and 10,11-(3)H-labeled retinoic acid into rats, three major metabolites were isolated from feces by column chromatography, thin-layer chromatography, and high-performance liquid chromatography, with concentrations in the microgram range. Mass spectrometry analysis identified them as all-trans-4-oxoretinoic acid, all-trans-5'-hydroxyretinoic acid, and 7-trans-9-cis-11-trans-13-trans-5'-hydroxyretinoic acid. For more complete metabolite/metabolite data on all-trans retinoic acid (a total of 8 metabolites), please visit the HSDB record page.
Known metabolites of retinoic acid include 5,6-epoxyretinoic acid, all-trans retinoic acid glucuronide, 18-hydroxyretinoic acid, and 4-hydroxyretinoic acid.
Retinoic acid is a known metabolite of retinaldehyde.
Hepatic
Half-life: 0.5–2 hours

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Biological half-life
The terminal elimination half-life of retinoic acid after the first dose is 0.5 to 2 hours in patients with acute promyelocytic leukemia (APL).
In patients with acute promyelocytic leukemia (APL) treated with oral retinoic acid, the terminal elimination half-life after the first dose has been reported to be 0.5–2 hours.

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Metabolism of Vitamin A and Formation of All-Trans Retinoic Acid [4]
Vitamin A is a dietary vitamin essential for normal development and vision. As early as 1881, Nicolai Luning hinted at the importance of vitamin A, discovering that purified proteins, fats, and carbohydrates could not sustain normal growth in mice unless milk was added to their diet. In 1917, Elmer Verner McCollum determined that a key component of milk was actually a "fat-soluble factor A," contrasting with the previously discovered "water-soluble factor B" (i.e., vitamin B). These findings enabled Danish pediatrician Carl Edvard Bloch to determine that vitamin A deficiency was the cause of night blindness (or dry eye). While vitamin A is an essential dietary vitamin, it is not itself the primary bioactive mediator for its function. Key mediators of vitamin A function have been identified as all-trans retinoic acid (atRA) and 11-cis-retinal. atRA is a regulator of gene transcription, while 11-cis-retinal acts as a chromophore for visual function. In this section, we will review the metabolic process of vitamin A being converted into various retinoids, with a focus on the formation of atRA (Figure 1).

Toxicity Summary
Identification and Uses: All-trans retinoic acid (retinoic acid) is indicated for the topical treatment of acne vulgaris. Retinoic acid capsules are indicated for inducing remission in patients with acute promyelocytic leukemia. Human Studies: Heart failure occurred in 6% of patients receiving retinoic acid, and cardiac arrest, myocardial infarction, stroke, and pulmonary hypertension occurred in 3%. There is a risk of arterial or venous thrombosis involving any organ system during the first month of retinoic acid treatment. Thromboembolic events, including fatal pulmonary embolism, have been reported in patients receiving retinoic acid. One patient receiving retinoic acid experienced a fatal thromboembolism while concurrently receiving antifibrinolytic drugs. Bone marrow necrosis, sometimes fatal, has been reported in patients taking hydroxyurea while receiving retinoic acid. Thrombocytosis has been rarely reported in patients receiving retinoic acid. Rapidly progressive leukocytosis occurs in approximately 40% of patients receiving retinoic acid. Retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (also known as APL differentiation syndrome) is characterized by fever, dyspnea, acute respiratory distress, weight gain, pulmonary infiltration, pleural and pericardial effusion, edema, liver failure, kidney failure, and multiple organ failure. This syndrome occurs in approximately 25% of APL patients receiving retinoic acid treatment. RA-APL syndrome is sometimes accompanied by decreased myocardial contractility and paroxysmal hypotension, with or without leukocytosis. In severe cases, progressive hypoxemia may occur, requiring intubation and mechanical ventilation, and there have been reports of death due to progressive hypoxemia and multiple organ failure. Animal studies: No evidence of carcinogenicity was found when retinoic acid was administered topically to mice at a daily dose of 0.025 mg/kg. When 0.017% and 0.035% retinoic acid preparations were administered topically to mice, squamous cell carcinoma and papilloma of the skin were observed in some female mice, while dose-related liver tumors were observed in male mice. In vitro studies of cultured rat embryos have shown that retinoic acid is a direct-acting teratogenic agent. Major defects involve the gill arches and somites. Retinoid-induced malformations of the jaw, ears, face, skull, eyes, and heart in humans and rodents are well-known. In mice subjected to a single oral dose of 100 mg/kg retinoic acid on day 9 or 11 of gestation and sacrificed on day 17 of gestation, 90% of the fetuses exhibited skeletal defects (limbs) and cleft palate. Evidence suggests that daily topical application of retinoic acid exceeding 1 mg/kg in rats is teratogenic (tail shortening or curvature). Daily dermal application of 10 mg/kg retinoic acid in rats has also been reported to cause skeletal abnormalities. Topical application of retinoic acid cream is associated with an increased incidence of cleft palate and hydrocephalus in rabbits. In rabbits treated with topical retinoic acid, some fetuses developed dome-shaped heads and hydrocephalus, typical manifestations of retinoid-induced fetal malformations in this species. In mice, doses above 0.7 mg/kg/day resulted in significant external, soft tissue, and skeletal changes. In rats, doses above 2 mg/kg/day, 7 mg/kg/day, 10 mg/kg/day, and 10 mg/kg/day all resulted in significant external, soft tissue, and skeletal changes. Subcutaneous injection in rabbits showed teratogenicity at a dose of 2 mg/kg/day, but not at 1 mg/kg/day. Neither in vivo nor in vitro (Ames assay) studies confirmed mutagenicity of retinoic acid. However, components in the microsphere formulation of this drug have shown potential genotoxicity and teratogenicity. Ecotoxicity studies: In Japanese flounder (Paralichthys olivaceus) 6–9 days after hatching, retinoic acid caused the most severe skeletal deformities among all tested retinoic acid isomers. Retinoic acid binds to α, β, and γ retinoic acid receptors (RARs). RAR-α and RAR-β are associated with the development and progression of acute promyelocytic leukemia and squamous cell carcinoma, respectively. RAR-γ is associated with the effects of retinoids on skin, mucous membranes, and bone. Although the exact mechanism of action of retinoic acid is not fully understood, existing evidence suggests that its effectiveness in treating acne is primarily attributed to its ability to improve abnormal follicular keratosis. Comedones form in hair follicles with an excess of keratinized epithelial cells. Retinoic acid promotes keratinocyte shedding and accelerates the shedding of follicular keratinocytes. By increasing the mitotic activity of follicular epithelial cells, retinoic acid also enhances the turnover rate of thin, loosely attached keratinocytes. Through these effects, comedone contents are expelled, and the formation of microcomedones (precursor lesions of acne vulgaris) is reduced. Retinoic acid is not a cell-dissolving agent, but it induces differentiation and inhibits the proliferation of acute promyelocytic leukemia (APL) cells in vitro and in vivo. When APL patients are treated systemically with retinoic acid, the treatment initially promotes the maturation of primitive promyelocytic cells derived from the leukemia clone, followed by the refilling of the bone marrow and peripheral blood with normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of retinoic acid in acute promyelocytic leukemia (APL) remains unclear.

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Interactions
This study used mouse mammary organ culture technology to investigate the effects of retinoids, including trans-retinoic acid, on prolactin-induced mammary gland structural differentiation. The thymus of BALB/c mice pretreated with steroids differentiated into alveolar structures within 6 days in the presence of insulin and prolactin. Trans-retinoic acid inhibited prolactin-induced changes in glandular structure. To determine whether 2,3,7,8-tetrachlorodibenzo-dioxin and retinoic acid would enhance or antagonize the teratogenic effects of another compound, C57BL/6N female rats were orally administered 10 mL of corn oil per kg body weight containing 2,3,7,8-tetrachlorodibenzo-dioxin (0-18 μg/kg), retinoic acid (0-200 mg/kg), or a combination of both compounds on day 10 or 12 of gestation. The female rats were sacrificed on day 18 of gestation, and toxicity and teratogenicity were assessed. The combined administration of 2,3,7,8-tetrachlorodibenzo-dioxin and retinoic acid did not result in maternal or fetal toxicity exceeding the expectations of either compound alone. On day 10 of gestation, low doses of retinoic acid induced cleft palate, while on day 12, low doses of 2,3,7,8-tetrachlorodibenzo-dioxin induced cleft palate. The sensitivity to hydronephrosis induced by 2,3,7,8-tetrachlorodibenzo-dioxin was similar on both days 10 and 12 of gestation. Limb bud defects were observed only when retinoic acid was administered on day 10 of gestation, but not when administered on day 12. Other soft tissue or skeletal malformations were unrelated to administration of 2,3,7,8-tetrachlorodibenzo-dioxin or retinoic acid. No effect was observed on the incidence or severity of retinoic acid-induced limb bud defects, nor did retinoic acid affect the incidence or severity of 2,3,7,8-tetrachlorodibenzodioxin-induced hydronephrosis. However, the combined use of xenobiotics and vitamins significantly increased the incidence of cleft palate. The dose-response curves for cleft palate induction were parallel on days 10 and 12 of gestation, suggesting some similarities in the mechanisms of action of the two compounds. However, the combined treatment produced a synergistic effect that varied with developmental stage and was tissue-specific. Patients receiving retinoic acid had an increased risk of developing pseudotumor cerebri (intracranial hypertension). Concomitant use of other drugs known to cause pseudotumor cerebri or intracranial hypertension, such as tetracyclines, may increase this risk in patients receiving retinoic acid. Concomitant use of hydroxyurea, which is cytotoxic to S-phase cells, and retinoic acid, which induces cell entry into S phase, may produce a synergistic effect, leading to extensive cell lysis. There have been reports of bone marrow necrosis, sometimes even fatal, in patients taking hydroxyurea while receiving retinoic acid treatment. Although some clinicians have combined hydroxyurea with retinoic acid to reduce leukocytosis, the safety and efficacy of this practice have not been established, and therefore caution is advised when using hydroxyurea in patients receiving retinoic acid treatment. For more complete data on interactions of all-trans retinoic acids (14 in total), please visit the HSDB record page. Non-human toxicity values: Oral LD50 in rats: 1960 mg/kg Intraperitoneal LD50 in rats: 96 mg/kg Subcutaneous LD50 in rats: 53 mg/kg Intravenous LD50 in rats: 78 mg/kg For more complete data on non-human toxicity values of all-trans retinoic acids (12 in total), please visit the HSDB record page.

[1]. Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis. PLoS One. 2016 Apr 14;11(4):e0153556.
[2]. Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor beta/delta. J Biol Chem. 2003 Oct 24;278(43):41589-92.
[3]. Retinoic acid induces neurogenesis by activating both retinoic acid receptors (RARs) and peroxisomeproliferator-activated receptor β/δ (PPARβ/δ). J Biol Chem. 2012 Dec 7;287(50):42195-205.
[4]. Retinoic acid synthesis and functions in early embryonic development. Cell Biosci. 2012 Mar 22;2(1):11.
[5]. A retinoic acid receptor alpha antagonist selectively counteracts retinoic acid effects. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7129-33.
[6]. Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19589-94

Therapeutic Uses
Anti-tumor drugs, keratolytic agents
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being studied); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Trans-retinoic acid is listed in the database.
Retinoic acid gels and creams are indicated for topical treatment of acne vulgaris. The safety and efficacy of this product for the long-term treatment of other conditions have not been established. /Included on US product label; Retinoic acid, for topical use/
Retinoic acid is used topically as a 0.05% or 0.1% cream to relieve photodamage-related skin changes (e.g., fine lines, patchy pigmentation, roughness). /Not included on US product label; Retinoic acid, for topical use/
For more complete data on the therapeutic uses of all-trans retinoic acid (9 types), please visit the HSDB record page.

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Drug Warning
/Black box warning/ Experienced physicians and institutions. Patients with acute promyelocytic leukemia (APL) are at high risk and taking retinoic acid capsules may cause serious adverse reactions. Therefore, retinoic acid capsules should only be used in APL patients under the strict supervision of an experienced physician treating acute leukemia in a healthcare facility with adequate laboratory and support services to monitor drug tolerance and protect and maintain patients impaired by drug toxicity, including respiratory impairment. Retinoic acid capsules should only be used if the physician believes the potential benefit to the patient outweighs the following known adverse treatment reactions. /Retinoic acid, systemic medication/
/Black box warning/ Retinoic acid-APL syndrome. Approximately 25% of patients with acute promyelocytic leukemia (APL) receiving retinoic acid capsules develop a syndrome called retinoic acid-APL (RA-APL), characterized by fever, dyspnea, acute respiratory distress, weight gain, chest infiltrates on X-ray, pleural and pericardial effusions, edema, and liver, kidney, and multiple organ failure. This syndrome is sometimes accompanied by decreased myocardial contractility and paroxysmal hypotension. Leukocytosis may or may not be present. Some cases require intubation and mechanical ventilation due to progressive hypoxemia, and some patients die from multiple organ failure. This syndrome usually occurs within the first month of treatment, but there are also reports of it occurring immediately after the first dose of retinoic acid capsules. Treatment for this syndrome is not well-established, but immediate administration of high-dose glucocorticoids upon suspicion of rheumatoid arthritis-associated acute promyelocytic leukemia (RA-APL) syndrome appears to reduce morbidity and mortality. Once early symptoms suggestive of the syndrome appear (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultation or imaging findings), regardless of white blood cell count, high-dose glucocorticoid therapy (dexamethasone 10 mg, intravenously, every 12 hours for 3 days or until symptom relief) should be initiated immediately. Most patients do not need to discontinue tretinoin capsules during treatment for RA-APL syndrome. However, for patients with moderate to severe RA-APL syndrome, temporary discontinuation of tretinoin capsule therapy should be considered. /Tretinoin, systemic medication/
/Black box warning/ Approximately 40% of patients develop rapidly progressive leukocytosis during tretinoin capsule therapy. Patients with elevated white blood cell counts at diagnosis (>5 × 10⁹/L) are at increased risk of further rapid increases in white blood cell count. Rapidly progressive leukocytosis is associated with an increased risk of life-threatening complications. If signs and symptoms of rheumatoid arthritis complicated with acute promyelocytic leukemia (RA-APL) syndrome appear, accompanied by leukocytosis, high-dose glucocorticoid therapy should be initiated immediately. Some researchers routinely add chemotherapy to retinoic acid capsule therapy when patients have a white blood cell count >5×10⁹/L at initial diagnosis, or when leukopenia is present at the start of treatment and the white blood cell count rapidly increases, and report a low incidence of RA-APL syndrome. For patients with a white blood cell count >5×10⁹/L, full-dose chemotherapy can be considered on day 1 or 2 to add to retinoic acid capsule therapy (anthracyclines can be added if there are no contraindications); for patients with a white blood cell count <5×10⁹/L, if the white blood cell count reaches ≥6×10⁹/L on day 5, or ≥10×10⁹/L on day 10, or ≥15×10⁹/L on day 28, full-dose chemotherapy can be added immediately. /Retinoic acid, systemic medication/
/Black box warning/ Teratogenic effects. Pregnancy category D. Taking retinoic acid capsules during pregnancy carries a high risk of serious birth defects. However, if retinoic acid capsules are determined to be the optimal treatment option for pregnant women or women of childbearing age, it must be ensured that the patient is fully informed of the potential risks to the fetus if pregnancy occurs, as well as the risk of contraceptive failure, and is informed of the need to use two reliable methods of contraception simultaneously during treatment and for one month after discontinuation of the medication. The patient must also confirm that they understand the necessity of dual contraception unless abstinence is chosen. A serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL should be performed on a blood or urine sample within one week before starting retinoic acid capsule treatment. If possible, retinoic acid capsule treatment should be postponed until a negative result is obtained. If treatment cannot be postponed, two reliable methods of contraception should be started immediately. Pregnancy tests and contraceptive counseling should be repeated monthly throughout the entire retinoic acid capsule treatment period. /Retinoic Acid, Systemic Use/
For more complete data on all-trans retinoic acid (44 items), please visit the HSDB record page.

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Pharmacodynamics
Retinoic acid is a vitamin A derivative that promotes cell generation, proliferation, and differentiation. When applied topically, retinoic acid regulates epidermal cell renewal and collagen production. It also prevents collagen loss, reduces inflammation, and inhibits the induction of matrix metalloproteinases (MMPs), enzymes that destroy collagen and elastin fibers. In short-term and long-term studies, topical application of retinoic acid at concentrations of 0.001% to 0.1% was associated with improved clinical symptoms of photoaging and fine lines, epidermal thickening, stratum corneum densification, and reduced melanin content. It also improves melanocyte differentiation and distribution, and promotes epidermal proliferation and angiogenesis. Oral retinoic acid has antitumor activity. Studies have shown that retinoic acid can induce tumor cell differentiation. It can induce cell differentiation and reduce the proliferation of acute promyelocytic leukemia (APL) cells in vitro and in vivo. In APL patients, retinoic acid promotes the initial maturation of primitive promyelocytes derived from leukemia clones, and subsequently, in patients who achieve complete remission, the bone marrow and peripheral blood are refilled with normal, polyclonal hematopoietic cells.

C20H28O2

300.4

300.208

C, 79.96; H, 9.39; O, 10.65

302-79-4

Retinoic acid-d5;78996-15-3;Retinoic acid;302-79-4;11-cis-Retinoic Acid-d5;Retinoic acid-d6;2483831-72-5

444795

Yellow to light-orange crystalline powder
Crystals from ethanol

1.0±0.1 g/cm3

462.8±14.0 °C at 760 mmHg

179-184ºC

350.6±11.0 °C

0.0±2.5 mmHg at 25°C

1.556

6.83

37.3

1

2

5

22

567

0

CC1(C)C(/C=C/C(C)=C/C=C/C(C)=C/C(O)=O)=C(C)CCC1

SHGAZHPCJJPHSC-YCNIQYBTSA-N

InChI=1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8+,16-14+

(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid

All-trans Retinoic Acid; Ro 5488; Ro-5488; tretinoin; ATRA; Renova; Aknefug; Atralin; Retin-A Micro; Tretinoina; ...; 302-79-4; Vitamin A acid; ATRA; TRA; Ro5488; alltrans vitamin A acid; betaretinoic acid; retinoic acid; TRA; trans retinoic acid; trans vitamin A acid; tretinoinum; Trade names: Avita; Renova; Aberel; Aknoten; RetinA; RetinA MICRO; Vesanoid. Foreign brand names: Airol; Eudyna; RetisolA; StievaA; Cordes Vas; Dermairol; EpiAberel; StievaA Forte; Vitinoin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

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 (8.32 mM) 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), 悬浮液； 超声和加热处理
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 (8.32 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), 悬浮液。
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 (8.32 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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配方 4 中的溶解度: 2.5 mg/mL (8.32 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*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 5 中的溶解度: 2.5 mg/mL (8.32 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*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 6 中的溶解度: 5 mg/mL (16.64 mM) in 50% PEG300 50% PBS (这些助溶剂从左到右依次添加，逐一添加), 悬浮液； 需要超声助溶并加热至 40°C。

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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。