(4Z,6R,7S)-4-ethylidene-7-hydroxy-7-(hydroxymethyl)-6-methyl-2,9-dioxa-14-azatricyclo[9.5.1.014,17]heptadec-11-ene-3,8-dione

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯类和类似物
• 英文名称: (4Z,6R,7S)-4-ethylidene-7-hydroxy-7-(hydroxymethyl)-6-methyl-2,9-dioxa-14-azatricyclo[9.5.1.014,17]heptadec-11-ene-3,8-dione
• 化学式: C₁₈H₂₅NO₆
• 分子量: 351.4
• InChiKey: BCJMNZRQJAVDLD-APNODFILSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  96.3
• 氢给体数：
  2
• 氢受体数：
  7

ADMET

代谢

使用 retrorsine 的研究表明，大鼠肝脏微粒体混合功能氧化酶系统确实形成了 n-氧化物和吡咯代谢物/retrorsine 吡咯。

Studies with retrorsine have confirmed the formation of the n-oxide and pyrrolic metabolites /retrorsine pyrrole/ by the mixed-function oxidase system of the microsomal fraction of rat liver.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在动物中，吡咯烷生物碱的主要代谢途径是：(a) 酯基的水解；(b) N-氧化；和(c) 吡咯烷环的脱氢生成吡咯衍生物。途径(a)和(b)被认为是解毒机制。途径(c)导致有毒代谢物。途径(a)发生在肝脏和血液中；途径(b)和(c)是通过微粒体混合功能氧化酶系统在肝脏中产生的。/吡咯烷生物碱/

In animals, the major metabolic routes of pyrrolizidine alkaloids are: (a) hydrolysis of the ester groups; (b) N-oxidation; and (c) dehydrogenation of the pyrrolizidine nucleus to pyrrolic derivatives. Routes (a) and (b) are believed to be detoxification mechanisms. Route (c) leads to toxic metabolites. Route (a) occurs in liver and blood; routes (b) and (c) are brought about in the liver by the microsomal mixed function oxidase system. /pyrrolizidine alkaloids/

来源:Hazardous Substances Data Bank (HSDB)

代谢

在体研究了大鼠体内吡咯里西啶生物碱（PAs）的代谢和排泄，特别是倒千里光碱（RET）和倒千里光碱-N-氧化物（RET-NO）。异色氨酸酸（INA）、吡咯代谢物、N-氧化物和倒千里光宁分别占给予RET的31.0%、10.3%、10.8%和0.39%。预先给予三正丙基磷酸酯（TOCP）对吡咯代谢物和INA的排泄没有影响。苯巴比妥（PB）增加了吡咯代谢物和INA的排泄，相应地减少了RET和N-氧化物的排泄；倒千里光宁的水平保持不变。当RET-NO通过腹腔注射给药时，与RET处理的相比，尿中吡咯代谢物、INA和RET的水平降低。口服给予RET-NO则显著提高了吡咯代谢物、INA和RET的水平。这些结果表明，酯酶水解在INA的形成中发挥作用较小，并且吡咯代谢物和INA的形成之间可能存在共同的代谢途径。

The in vivo metabolism and excretion of the urinary metabolites from the pyrrolizidine alkaloids (PAs), retrorsine (RET) and retrorsine-N-oxide (RET-NO) have been studied in rats. Isatinecic acid (INA), pyrrolic metabolites, N-oxides and retronecine accounted for 31.0, 10.3, 10.8 and 0.39% of the administered RET. Predosing rats with triorthocresyl phosphate (TOCP), had no effect on the excretion of pyrrolic metabolites and INA. Phenobarbital (PB) increased the excretion of both pyrrolic metabolites and INA with a corresponding decrease in the excretion of RET and N-oxides; the retronecin levels remained unaltered. When RET-NO was administered i.p., the urinary levels of pyrrolic metabolites, INA and RET were decreased relative to those treated with RET. The p.o. administration of RET-NO produced significantly higher levels of pyrrolic metabolites, INA and RET. These results suggest that esterase hydrolysis plays a minor role in the formation of INA and that a common metabolic pathway may exist between pyrrolic metabolites and INA formation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

...Retrorsine被给予一组年轻的成年雄性大鼠，并检查了它对广泛研究的肝脏CYP同种物（跨越四个家族）以及关键酶CYP还原酶的mRNA和蛋白质的诱导或增强表达。与未经处理的对照组大鼠相比，Retrorsine处理的大鼠肝脏微粒体中通常表达的CYPs 1A2、2B1/2和2E1的蛋白质水平显著增加（P<0.05），但CYP 4A3、CYP 3A1和CYP还原酶的蛋白质水平在Retrorsine处理后没有变化。此外，在对照组大鼠肝脏中无法检测到的CYP 1A1的mRNA和蛋白质在Retrorsine暴露后被诱导。目前的研究结果表明，在大鼠中，Retrorsine暴露增强了或诱导了肝脏CYPs 1A1、1A2、2E1和2B1/2的表达，这表明这些酶中的一个或多个可能参与了Retrorsine的代谢。

...Retrorsine was administered to a cohort of young adult male rats and examined induction or enhanced expression of mRNA and protein for widely studied hepatic CYP isoforms spanning four families together with the essential enzyme CYP reductase. The protein levels of normally expressed CYPs 1A2, 2B1/2, and 2E1 increase significantly in rat liver microsomes from retrorsine-treated rats compared to untreated control rats (P< 0.05), but protein levels of CYP 4A3, CYP 3A1, and CYP reductase were unchanged after retrorsine treatment. In addition, CYP 1A1 mRNA and protein, which are not detectable in the livers of control rats, were induced after retrorsine exposure. The results of the present study demonstrate enhanced or induced expression of hepatic CYPs 1A1, 1A2, 2E1, and 2B1/2 in response to retrorsine exposure in rats, suggesting that one or more of these enzymes may be involved in retrorsine metabolism.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

没有关于人类的数据。动物致癌性的证据有限。总体评估：第3组：该物质对人类致癌性无法分类。

No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌剂：雷斯托辛

IARC Carcinogenic Agent:Retrorsine

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：第3组：无法归类其对人类致癌性

IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity to humans

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构专著：第10卷：（1976年）一些天然存在的物质

IARC Monographs:Volume 10: (1976) Some Naturally Occurring Substances

来源:International Agency for Research on Cancer (IARC)

毒理性

• 相互作用

...对Porton Wistar大鼠幼崽通过胃管单次给予30毫克/千克体重的 retrorsine，给药后100天接受全身400拉德辐射，共31只大鼠...在25只幸存者中，有5个肝母细胞瘤，5个乳腺肿瘤，2个肾细胞癌和1个肝细胞癌伴肺转移，1个肺癌，1个结肠癌，1个脾血管内皮瘤，1个肱骨骨肉瘤，1个白血病和1个颈部梭形细胞肿瘤的案例... /没有对照组出现/

...Weanling Porton Wistar rats were given single doses of 30 mg/kg body weight retrorsine by stomach tube...with whole-body irradiation of 400 rads 100 days after dosing, in 31 rats... In 25 survivors, there were 5 hepatomas, 5 mammary tumors, 2 renal carcinomas and 1 case each of carcinoma of the liver with pulmonary metastases, carcinoma of the lung, carcinoma of the colon, hemangioendothelioma of the spleen, osteosarcoma of the humerus, leukemia and spindle-cell tumor of the neck... /no controls presented/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在动物研究中，最高浓度被发现于肝脏、肺、肾脏和脾脏。/吡咯烷生物碱/

In animal studies highest concentrations were found in the liver, lungs, kidneys and spleen. /pyrrolizidine alkaloids/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

当向大鼠腹腔注射吡咯烷生物碱、反式 retrorsine 60 mg/kg、反式 retrorsine N-氧化物 60 mg/kg 时，24小时内，剂量的0.2-12.4% 以代谢吡咯的形式随尿液排出。生物碱的肝毒性与其在体内产生的吡咯量之间存在大致的相关性。当大鼠口服或腹腔注射反式 retrorsine 50 mg/kg 并在给药后不同时间处死，代谢吡咯被发现强烈结合在肝脏上，并且到较少程度上结合在肺和其他器官上，这种结合在形成后持续48小时或更长时间。

When pyrrolizidine alkaloids, retrorsine 60 mg/kg, retrorsine n-oxide 60 mg/kg were administered ip to rats, 0.2-12.4% of the doses were excreted in the urine within 24 hr as metabolic pyrroles. There was a rough correlation between the hepatotoxicity of alkaloids and the amount of pyrroles to which they gave rise to in vivo. When rats were dosed orally or ip with retrorsine 50 mg/kg and sacrificed after various times, metabolic pyrroles were found bound strongly to the liver, and to /lesser/ extent the lung and other organs, for 48 hr or more after being formed.

来源:Hazardous Substances Data Bank (HSDB)