(1R,3'S,4R,6R,7R,17R)-7-hydroxy-3',6,7-trimethylspiro[2,9-dioxa-14-azatricyclo[9.5.1.014,17]heptadec-11-ene-4,2'-oxirane]-3,8-dione

• 分子结构分类: 有机化合物 - 生物碱及其衍生物
• 英文名称: (1R,3'S,4R,6R,7R,17R)-7-hydroxy-3',6,7-trimethylspiro[2,9-dioxa-14-azatricyclo[9.5.1.014,17]heptadec-11-ene-4,2'-oxirane]-3,8-dione
• 化学式: C₁₈H₂₅NO₆
• 分子量: 351.4
• InChiKey: IAPHXJRHXBQDQJ-OCUBZGOOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  25
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  88.6
• 氢给体数：
  1
• 氢受体数：
  7

ADMET

代谢

一般来说，肝脏毒性的吡咯烷生物碱在大鼠肝脏中被代谢，产生水解产物、N-氧化物和脱氢吡咯里西啶（吡咯衍生物）。根据目前的证据，后一组物质似乎介导了生物碱的大多数毒性反应。这些吡咯衍生物是由肝细胞的混合功能氧化酶产生的。从生物碱（例如雅各宾碱...）的 retronecine 酯形成的初始产物很可能是脱氢生物碱。脱氢生物碱是高度反应性的烷基化剂，它们会立即与细胞成分反应，产生可溶的或结合的次级代谢物，或者水解生成脱氢氨基醇。/吡咯里西啶生物碱/

In general, the hepatotoxic pyrrolidine alkaloids are metabolized in rat liver to give hydrolysis products, n-oxides and dehydropyrrolizidine (pyrrolic) deriv. The latter group appears on current evidence to mediate most of toxic reactions of alkaloids. These pyrrolic deriv are produced by mixed-function oxidases of liver cells. Initial product formed from alkaloids that are esters of...retronecine (eg, jacobine...) is very probably the dehydroalkaloid. Dehydroalkaloids are highly reactive alkylating agents which react immediately with cell constituents to give soluble or bound secondary metabolites or which hydrolyze to dehydroaminoalcohol. /pyrrolizidine alkaloids/

来源:Hazardous Substances Data Bank (HSDB)

代谢

长时间注射苯巴比妥（pb）对千里光（sj）毒性的影响在绵羊身上进行了研究。结果表明，pb诱导的混合功能氧化酶并未增加绵羊对sj中毒的易感性。绵羊具有高活性的肝微粒体环氧化物水解酶，这可能是它们对sj中毒有抵抗力的原因。

The effect of prolonged phenobarbital (pb) administration on the toxicity of Senecio jacobaea (sj) was studied in sheep. Results suggested that mixed-function oxidase induction by pb does not increase the susceptibility of sheep to sj intoxication. Sheep possess a high activity of hepatic microsomal epoxide hydrolase which could account for their resistance to sj intoxication.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在伪一级反应条件下，对一系列半合成吡咯酯和吡咯啉生物碱的烷基化活性进行了比较。雅各宾吡咯（雅各宾的一种活性代谢物）的烷基化数据符合简单的一级速率表达式。雅各宾吡咯反应速率的大幅增加提示了靠近C-7酯基的环氧环可能产生的电子场效应。

Comparison is made of the alkylating activities of a series of semi-synthetic pyrrole esters and pyrrole derivatives of pyrrolizidine alkaloids under pseudo-first-order reaction conditions. Data for alkylation by jacobine pyrrole (a reactive metabolite of jacobine) fit a simple first-order rate expression for product formation. The large increase in reaction rate for jacobine pyrrole is suggestive of an electronic field effect due to the epoxide ring in proximity to the C-7 ester moiety.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

没有关于人类的数据。动物致癌性证据不足。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. Inadequate 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：雅各宾

IARC Carcinogenic Agent:Jacobine

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：对其对人类的致癌性无法分类

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论集：第10卷：（1976年）一些自然存在的物质

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

硫酸锌（以氯化锌形式，72微摩尔/千克）连续三天通过腹腔注射给药，最后一次给药后16小时，单次腹腔注射从千里光中提取的纯化混合吡咯烷生物碱（PAs）（80、120或160毫克/千克）。在给予PAs（120毫克/千克）后，血浆谷氨酸-草酰乙酸转氨酶增加了7倍，谷氨酸-丙酮酸转氨酶增加了12倍，而锌预处理将这些增加分别降至2.4倍和2.1倍。当PAs剂量为80或120毫克/千克时，锌预处理要么减轻了PAs引起的肝脏坏死严重程度，要么完全消除了坏死。这些结果表明锌对PAs肝毒性具有保护作用。这种保护作用与肝脏金属硫蛋白的显著增加以及肝脏细胞色素P-450含量、氨苯砜N-脱甲基酶活性和PAs体外微粒体转化为吡咯的显著减少有关。

Zinc, 72 umol/kg as zinc chloride, was administered ip for 3 consecutive days, followed 16 hours after the last dose by a single ip injection of purified mixed pyrrolizidine alkaloids (pa's) (80, 120, or 160 mg/kg) obtained from tansy ragwort. A 7-fold increase in plasma glutamic-oxaloacetic transaminase and 12-fold increase in glutamic-pyruvic transaminase after pa's (120 mg/kg) were reduced to 2.4 and 2.1-fold, respectively by zinc pretreatment. The pa-induced liver necrosis was either reduced in severity or abolished by zinc when the pa dose was 80 or 120 mg/kg. These results suggest a protective effect of zinc against pa hepatotoxicity. The effect was associated with a marked increase in liver metallothionein and a significant decrease in hepatic cytochrome P-450 content, aminopyrine n-demethylase activity, and in vitro microsomal conversion of the pa's to pyrroles.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

饮食中添加铜和锌对兔子的吡咯烷生物碱（PAs）的排泄没有影响。从千里光属植物Jacobaea分离出的PAs在体外实验中能够轻易地穿越空肠和回肠的隔离翻转型囊的粘膜，逆浓度梯度转移。这些结果表明，饮食中千里光属植物对矿物质代谢改变的影响并不是由于胃肠道矿物质吸收的变化。此外，兔子对饮食中千里光属植物的抵抗并不是由于吡咯烷生物碱的胃肠道吸收低，而是由于高效的尿液排出。

Excretion of pyrrolizidine alkaloids (pa's) in diet of rabbits was not affected by the addition of copper and zinc to the diet. Isolated pa's from Senecio jacobaea were found to be readily transferred across the mucosa of isolated everted sacs of jejunum and ileum in vitro against a concentration gradient. These results suggest that the effects of dietary Senecio jacobaea on alterations in mineral metabolism are not due to changes in GI mineral absorption. In addition, it appears that the resistance of rabbits to dietary Senecio jacobaea intoxication is not caused by low GI absorption of pyrrolizidine alkaloids, but rather by efficient urinary elimination.

来源:Hazardous Substances Data Bank (HSDB)