红青霉毒素B | 21794-01-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 红青霉毒素B
• 中文别名: 红青霉毒素 B
• 英文名称: Rubratoxin B
• 英文别名: (2R,3S,10S)-2-hydroxy-3-[(1R)-1-hydroxyheptyl]-10-[(S)-hydroxy-[(2S)-6-oxo-2,3-dihydropyran-2-yl]methyl]-6,14-dioxatricyclo[10.3.0.04,8]pentadeca-1(12),4(8)-diene-5,7,13,15-tetrone
• CAS: 21794-01-4
• 化学式: C₂₆H₃₀O₁₁
• 分子量: 518.5
• InChiKey: ZJTBTDVZNGBSNG-RETZLTROSA-N

物化性质

• 熔点：
  176°C
• 沸点：
  522.6°C (rough estimate)
• 密度：
  1.2767 (rough estimate)
• 颜色/状态：
  CRYSTALIZES FROM DIETHYL ETHER AS ROSETTES OF NEEDLES; FROM BENZENE & ETHYL ACETATE AS LONG LATHES; HEXAGONAL PLATES FROM AMYL ACETATE
• 稳定性/保质期：

  STABLE AT ROOM TEMP /RUBRATOXINS/

• 旋光度：
  Specific optical rotation: +67 deg (acetone, 20 °C, c=2)
• 分解：
  When heated to decomposition it emits acrid smoke and irritating fumes.
• 解离常数：
  PKA= 4.69

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  174
• 氢给体数：
  3
• 氢受体数：
  11

ADMET

代谢

三羧酸循环不仅用于将葡萄糖完全氧化成二氧化碳和水，还为一些次级代谢物的生物合成提供中间体，包括类胡萝卜素毒素...第一步涉及癸酸与草酰乙酸的缩合，这一过程类似于柠檬酸的形成。随后的脱水、脱羧和氧化导致形成一个中间酐，该酐二聚化并在进一步氧化后形成类胡萝卜素毒素A。氧气功能在哪个阶段引入尚不清楚，特别是，这样一个假设将意味着α,β-不饱和γ-内酯的羧基来自乙酸盐的甲基碳。/类胡萝卜素毒素/

AS WELL AS SERVING TO COMPLETE THE OXIDATION OF GLUCOSE TO CO2 & WATER, THE TRICARBOXYLIC ACID CYCLE ALSO PROVIDES INTERMEDIATES FOR THE BIOSYNTHESIS OF SOME SECONDARY METABOLITES, INCL THE RUBRATOXINS... THE FIRST STEP INVOLVES CONDENSATION OF DECANOIC ACID WITH OXALOACETIC ACID IN A MANNER ANALOGOUS TO THE FORMATION OF CITRIC ACID. SUBSEQUENT DEHYDRATION, DECARBOXYLATION & OXIDATION LEAD TO AN INTERMEDIATE ANHYDRIDE WHICH DIMERIZES TO FORM, AFTER FURTHER OXIDATION, RUBRATOXIN A. AT WHAT STAGE THE OXYGEN FUNCTIONS ARE INTRODUCED IS NOT CLEAR, &, IN PARTICULAR, SUCH A HYPOTHESIS WOULD MEAN THAT THE CARBOXYL GROUP OF THE ALPHA,BETA-UNSATURATED GAMMA-LACTONE WOULD BE DERIVED FROM THE METHYL CARBON OF ACETATE. /RUBRATOXINS/

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏代谢Ruby毒素。存在多种代谢物。在大鼠中，葡萄糖苷酸和硫酸盐结合物被排入胆汁，在肠道中显然被水解，母体毒素可能通过肠肝循环再次被吸收。还形成了未知的代谢物。/Ruby毒素/

THE LIVER METABOLIZES RUBRATOXINS. THERE ARE A NUMBER OF METABOLITES. IN RATS, GLUCURONIDE & SULFATE CONJUGATES ARE EXCRETED IN BILE, APPARENTLY HYDROLYZED IN THE INTESTINE, & THE PARENT TOXIN MAY BE RESORBED IN AN ENTEROHEPATIC CYCLE. UNKNOWN METABOLITES ARE ALSO FORMED. /RUBRATOXINS/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鲁比拉毒素B具有细胞毒性，阻碍细胞增殖，并诱导细胞凋亡。它还抑制基质金属蛋白酶-2和-9的活性。鲁比拉毒素B能导致多核糖体复合物的解聚，可能是通过抑制与多核糖体与膜结合位点相关的酶。它还被证明能结合一些肝脏微粒体，并抑制Na+/K+-转运ATP酶。鲁比拉毒素B可以抑制蛋白磷酸酶2A，发挥抗肿瘤和抗转移作用。抑制可能导致CREB的磷酸化，随后通过刺激T细胞释放白细胞介素-2来激活自然杀伤细胞，从而有助于抗转移效果。干扰细胞粘附的焦点粘附激酶磷酸化和桩蛋白磷酸化可能是另一种抗转移效果。霉菌毒素通常能够通过人类有机阴离子转运体（hOATs）和人类有机阳离子转运体（hOCTs）进入肝脏和肾脏。它们还可以抑制这些转运体对阴离子和阳离子的摄取，干扰内源代谢物、药物和包括它们自己在内的外源物质的分泌。这导致细胞内毒性化合物的积累增加，造成肾毒性和肝毒性。（A2985, A2986, A2987, A3014）

Rubratoxin B is cytotoxic, hinders cell proliferation, and induces apoptosis. It also inhibits the activity of matrix metalloproteinase-2 and -9. Rubratoxin B causes disaggregation of the polyribosome complex, likely by inhibiting an enzyme associated with the site of polyribosome binding to the membrane. It has also been shown to bind to some hepatic microsomes and inhibit Na+/K+-transporting ATPases. Rubratoxin B can inhibit protein phosphatase 2A, exerting antitumor and antimetastatic effects. Inhibition may cause the phosphorylation of CREB and subsequent activation of natural killer cells via the stimulation of interleukin-2 release from T cells, contributing to antimetastatic effects. Focal adhesion kinase phosphorylation and paxillin phosphorylation that interfere with cell adhesion could be another antimetastatic effect. Mycotoxins are often able to enter the liver and kidney by human organic anion transporters (hOATs) and human organic cation transporters (hOCTs). They can also inhibit uptake of anions and cations by these transporters, interefering with the secretion of endogenous metabolites, drugs, and xenobiotics including themselves. This results in increased cellular accumulation of toxic compounds causing nephro- and hepatotoxicity. (A2985, A2986, A2987, A3014)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

Rubratoxin B 是肝脏毒性、肾脏毒性和脾脏毒性，可导致充血性、出血性和退行性病变。

Rubratoxin B is hepatotoxic, nephrotoxic, and splenotoxic, causing congestive, hemorrhagic and degenerative lesions. (A2985, A2986)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

口服、皮肤、吸入和注射（污染药物）。

Oral, dermal, inhalation, and parenteral (contaminated drugs). (A3101)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 副作用

职业性肝毒素 - 第二性肝毒素：在职业环境中的毒性效应潜力是基于人类摄入或动物实验的中毒案例。

Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

吸收、分配和排泄

放射性标记的rubratoxin B（14）C在小鼠和大鼠中的排泄模式...在最初的24小时内排出了40-50%的放射性剂量。主要的排泄途径是通过呼吸的CO2，在小鼠中占给药（14）C的30%，在大鼠中占35%。6到9%通过尿液排出；粪便中存在的放射性活性较少。来自rubratoxin的放射性活性在给药后一小时内以最大水平出现在肝脏和肾脏中；其他器官中发现了较小的量。放射性活性的浓度在肝脏组织中最高。

EXCRETION PATTERNS OF (14)C DERIVED FROM RADIOLABELED RUBRATOXIN B...IN MICE & RATS...EXCRETED 40-50% OF THE ADMIN RADIOACTIVITY DURING THE INITIAL 24 HR. A MAJOR EXCRETORY ROUTE WAS RESP CO2 WHICH ACCOUNTED FOR 30% OF THE ADMIN (14)C IN MICE & 35% IN RATS. 6 TO 9% WAS EXCRETED IN THE URINE; LESS RADIOACTIVITY WAS PRESENT IN FECES. RADIOACTIVITY DERIVED FROM RUBRATOXIN WAS PRESENT AT MAX LEVELS IN LIVER & KIDNEYS ONE HR AFTER ADMIN; SMALLER AMT WERE FOUND IN OTHER ORGANS. THE CONCN OF RADIOACTIVITY WAS GREATEST IN LIVER TISSUE.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

(14)C标记的放射活性红毒素B在小鼠和大鼠中的排泄模式...在注射后1/2小时内，所有可检测到的放射性活性都存在于微粒体上清液中。在前2小时内，线粒体中的放射性活性逐渐增加，与此同时微粒体上清液中的放射性活性逐渐减少。在24小时时，线粒体部分含有大约14%的肝脏放射性活性，而80%的放射性活性仍留在溶液部分。在24小时期间，微粒体部分含有4%到10%的肝脏放射性活性。

EXCRETION PATTERNS OF (14)C DERIVED FROM RADIOLABELED RUBRATOXIN B...IN MICE & RATS. ...ALL DETECTABLE RADIOACTIVITY PRESENT IN THE LIVER 1/2 HR AFTER INJECTION WAS IN THE MICROSOMAL SUPERNATANT FLUID. WITHIN THE FIRST 2 HR, INCR AMT OF RADIOACTIVITY WERE FOUND IN THE MITOCHONDRIA WITH A CONCOMITANT DECR IN THE MICROSOMAL SUPERNATANT FLUID. AT 24 HR, THE MITOCHONDRIAL FRACTION CONTAINED APPROX 14% OF THE LIVER RADIOACTIVITY WITH 80% REMAINING IN THE SOL FRACTION. THE MICROSOMAL FRACTION CONTAINED 4 TO 10% OF THE LIVER RADIOACTIVITY DURING THE 24-HR PERIOD.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

排泄物、肾脏和肝脏组织浓度以及从血浆浓度估算的药代动力学参数对给予单次IP剂量的(14)C-红毒素B的大鼠进行了测定（0.05毫克溶解于丙二醇中）。到7天时，80%的管理放射性已排泄入尿液（41.7%）和粪便（38.7%）。尿排泄主要是以原型化合物为主，占7天内排泄放射性物质的75%。肾脏中放射性物质的消除是单相的，半衰期为97.35小时。肝脏中放射性物质的消除是双相的，慢相的半衰期为13.66小时。红毒素B及其衍生放射性物质（来自原型化合物和代谢物）从血浆中的消除也是双相的。消除的快速相半衰期为2.57和1.08小时，慢相半衰期为60.80和100.46小时，分别对应红毒素B和(14)C-红毒素B衍生放射性物质。长的血浆半衰期提示存在肠肝循环。放射性物质浓度在肝脏中最高的是1小时，在血浆中最高的是2小时。除了注射后最初的几小时外，肝脏中的放射性物质浓度从未显著超过血浆中的浓度，这表明存在被动吸收过程。

EXCRETION, TISSUE CONCN IN KIDNEY & LIVER, & PHARMACOKINETIC PARAMETERS ESTIMATED FROM PLASMA BLOOD CONCN WERE DETERMINED FOR RATS GIVEN A SINGLE IP DOSE OF (14)C-RUBRATOXIN B (0.05 MG DISSOLVED IN PROPYLENE GLYCOL). BY 7 DAYS, 80% OF ADMIN RADIOACTIVITY WAS EXCRETED INTO THE URINE (41.7%) & FECES (38.7%). URINARY EXCRETION WAS PRIMARILY AS THE PARENT COMPOUND, ACCOUNTING FOR 75% OF RADIOACTIVITY EXCRETED BY 7 DAYS. ELIMINATION OF RADIOACTIVITY FROM KIDNEYS WAS MONOPHASIC WITH T/2 OF 97.35 HR. ELIMINATION OF RADIOACTIVITY FROM LIVER WAS BIPHASIC, WITH T/2 OF 13.66 HR FOR THE SLOW PHASE. ELIMINATION OF RUBRATOXIN B & (14)C-RUBRATOXIN B-DERIVED RADIOACTIVITY (RADIOACTIVITY DERIVED FROM BOTH THE PARENT COMPOUND & METABOLITES) FROM PLASMA WAS BIPHASIC. THE RAPID PHASES OF ELIMINATION HAD T/2 OF 2.57 & 1.08 HR, & SLOW PHASES HAD T/2 OF 60.80 & 100.46 HR FOR RUBRATOXIN B & (14)C-RUBRATOXIN B-DERIVED RADIOACTIVITY RESPECTIVELY. THE LONG PLASMA T/2 IS SUGGESTIVE OF ENTEROHEPATIC CIRCULATION. THE CONCN OF RADIOACTIVITY WAS GREATEST AT 1 HR IN LIVER & 2 HR IN PLASMA. EXCEPT FOR THE FIRST FEW HR FOLLOWING INJECTION, THE CONCN OF RADIOACTIVITY IN LIVER NEVER EXCEEDED SIGNIFICANTLY THAT IN THE PLASMA, SUGGESTING A PASSIVE ABSORPTION PROCESS.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  Xn
• 危险类别码：
  R22
• RTECS号：
  GX9275000
• 包装等级：
  III
• 危险类别：
  6.1(b)