鬼臼毒素 | 518-28-5

• 物质功能分类: 原料药 - 抗肿瘤药 - 天然来源类抗肿瘤药
• 分子结构分类: 有机化合物 - 木脂素、新木脂素和相关化合物 - 木脂素内酯
• 中文名称: 鬼臼毒素
• 中文别名: 鬼臼脂毒；(5R,5aR,8aR,9R)-5R-5,8,8a,9-四氢-9-羟-5-(3,4,5-三甲氧苯基)呋喃(3",4":6,7)萘并-[2,3-d]-1,3-；鬼臼酯素；足叶草毒素；普达非伦毒素；(5R,5aR,8aR,9R)-5R-5,8,8a,9-四氢-9-羟-5-(3,4,5-三甲氧苯基)呋喃(3',4':6,7)萘并-[2,3-d]-1,3-间二氧杂环烯-6(5aH)-酮
• 英文名称: podofilox
• 英文别名: (-)-podophyllotoxin；PPT；PDT；podo；(5R,5aR,8aR,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one
• CAS: 518-28-5
• 化学式: C₂₂H₂₂O₈
• mdl: MFCD00075290
• 分子量: 414.412
• InChiKey: YJGVMLPVUAXIQN-XVVDYKMHSA-N

物化性质

• 熔点：
  183-184 °C (lit.)
• 比旋光度：
  -110.7 º (c=1, CHCl3)
• 沸点：
  453.31°C (rough estimate)
• 密度：
  1.2649 (rough estimate)
• 溶解度：
  DMSO:15.0(最大浓度 mg/mL);36.2(最大浓度 mM)
• LogP：
  2.010
• 物理描述：
  Solid
• 颜色/状态：
  Solvated crystals
• 蒸汽压力：
  8.3X10-15 mm Hg at 25 °C /Estimated/
• 旋光度：
  Specific optical rotation = -132.7 deg @ 20 °C/D, chloroform, 2%
• 碰撞截面：
  190.1 Ų [M+H-H2O]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.409
• 拓扑面积：
  92.7
• 氢给体数：
  1
• 氢受体数：
  8

ADMET

代谢

半衰期：1.0至4.5小时。

Half Life: 1.0 to 4.5 hours.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

鉴定：足叶草是一种皮肤科药物。物质来源：北美品种的足叶草（Podophyllum peltatum，又称曼陀罗或五月苹果植物）的根和根状茎的干燥树脂；活性成分包括木脂素，包括足叶毒素（20%）、α-足叶酸（10%）和β-足叶酸（5%）。它是一种淡棕色至绿黄色的可溶于水、酒精、氯仿、丙酮、温苯和冰醋酸的固体粉末。适应症：用于去除疣或鸡眼。描述：足叶草树脂具有抗有丝分裂作用，主要用于局部治疗生殖器疣（尖锐湿疣）。足叶草树脂曾被用于外阴、会阴和尿道内疣的治疗，但不应用于宫颈或尿道疣。必须小心避免应用到健康组织。足叶草树脂也用于治疗足底疣的软膏。足叶草树脂曾被用作泻药，但口服后会有明显的催吐作用，对肠粘膜极为刺激，并产生剧烈的蠕动。它已被更少毒性的泻药所替代。人体暴露：主要风险和靶器官：足叶草树脂的主要活性成分，足叶毒素，是一种脂溶性化合物，容易穿过细胞膜。足叶毒素及其衍生物是强大的细胞毒素，能够抑制细胞有丝分裂和脱氧核糖核酸（DNA）合成，其方式与秋水仙碱类似。细胞分裂被阻止，其他细胞过程受损，逐渐导致细胞破坏和组织破坏。局部足叶草容易被系统吸收，并能穿过胎盘。局部应用或口服摄入可能会导致多系统毒性效应。临床效应总结：系统性中毒的特征包括恶心和呕吐（可能是持续的）、呼吸急促、发热、昏迷、心动过速、低血压、麻痹性肠梗阻、少尿、肾衰竭、白细胞增多、白细胞减少、周围神经病和死亡。禁忌症：妊娠：局部足叶草被系统吸收并穿过胎盘屏障。它与人体的先天性畸形有关。暴露途径：口服：即使会引起恶心和呕吐，也容易被吸收。皮肤：局部应用后会被系统吸收，特别是如果皮肤表面不完整。眼睛：通过粘膜非常好吸收。暴露途径的吸收：口服吸收：足叶草摄入后非常好且快速吸收。在一例死亡病例中，病人在医生的办公室摄入了10到11克25%的足叶草溶液。他立即被给予艾佩卡糖浆并在摄入后45分钟呕吐。他还被给予活性炭和柠檬酸镁。尽管进行了血液灌流，他在摄入后39小时死亡。皮肤吸收：文献中有几例局部应用足叶草后发生系统性中毒的案例。在这种情况下，症状出现的延迟在2到24小时之间。暴露途径的分布：由于足叶毒素可溶于水，可以预测分布体积较小。此外，血液灌流后没有观察到反跳效应。代谢：无可用数据。在一例报告中，在血液灌流前、中、后检查了患者血浆中的足叶毒素。在开始血液灌流前的一段时间内，血浆中足叶毒素浓度迅速下降，提示快速代谢。在几例病例报告中症状出现的延迟可能表明足叶毒素的代谢物比足叶毒素本身更有毒。这项研究在血液灌流期间测量了一种代谢物，但在分析中发现并移除了几种其他可能的代谢物。作用方式：毒动力学：足叶草树脂是一种有效的有丝分裂毒素，能以与秋水仙碱类似的方式阻止有丝分裂中期。人类中毒是由于局部应用或摄入商业提取物所致。过度暴露会导致神经、胃肠和血液毒性，偶尔会导致死亡。很少情况下，食用未成熟果实或植物部分会导致腹泻，主要是腹泻。成熟果实不会产生毒性。足叶草是一种角质软化剂，具有腐蚀性和泻药作用。足叶草是一种抗有丝分裂剂。它结合到微管蛋白上，微管蛋白是微管蛋白亚单位，与秋水仙碱结合在同一位点或与秋水仙碱结合位点有较大重叠。足叶毒素的抗有丝分裂作用可能是由干扰染色体的运动引起的。足叶毒素的分子机制是通过足叶毒素与微管蛋白的结合破坏有丝分裂纺锤体的微管。足叶草具有腐蚀性，但其作用与大多数腐蚀剂不同，因为其效果既不是直接的也不是立即的：相反，细胞分裂被阻止和其他细胞过程受损后，细胞破坏和组织侵蚀会缓慢发生。人体毒性：成人：大多数局部应用足叶草后发生系统性中毒的病例涉及女性，其中一些是致命的。在足叶草应用于大面积或过量、或药物与皮肤或粘膜长时间接触后，会发生严重的系统性毒性。当足叶草应用于脆弱、出血或最近活检的疣，或药物意外应用于正常皮肤或受影响区域周围的粘膜时，系统性中毒的风险可能会增加。在局部应用或摄入足叶草后，可能会出现肾衰竭和肝毒性

IDENTIFICATION: Podophyllum is a dermatological medication. Origin of the substance: Dried resin from the roots and rhizomes of Podophyllum peltatum (Mandrake or May apple plant) the North American variety; active ingredients are lignans including podophyllotoxins (20%), alpha-peltatin (10%) and beta-peltatin (5%). It is a light brown to greenish yellow solid powder soluble in water, alcohol, chloroform, acetone, warm benzene and glacial acetic acid. Indications: Wart or corn removal preparation. Description: Podophyllum resin has an antimitotic action and is used principally as a topical treatment for ano-genital warts (condylomata acuminata). Podophyllum resin has been used on external genital, perianal and intrameatal warts, but should not be used on cervical or urethral warts. Care must be taken to avoid application to healthy tissue. Podophyllum resin is also used in an ointment for plantar warts. Podophyllum resin has been used as a laxative, but when taken by mouth, it has a marked purging action and it is highly irritating to the intestinal mucosa and produces violent peristalsis. It has been superseded by less toxic laxatives. HUMAN EXPOSURE: Main risk and target organs: Podophyllum resin's major active constituent, podophyllotoxin, is a lipid soluble compound that readily crosses cell membranes. Podophyllotoxin and its derivatives are potent cytotoxic agents that inhibit cell mitosis and deoxyribonucleic acid (DNA) synthesis in a manner similar to that of colchicine. Cell division is arrested and other cellular processes are impaired, gradually resulting in the disruption of cells and destruction of the tissue. Topical podophyllum is easily absorbed systemically and can cross the placenta. Either local application or oral ingestion may produce multisystem toxic effects. Summary of clinical effects: Features of systemic toxicity include nausea and vomiting (which may be persistent), tachypnea, fever, stupor, coma, tachycardia, hypotension, paralytic ileus, oliguria, renal failure, leukocytosis, leucopenia, peripheral neuropathy and death. Contraindications: Pregnancy: topical podophyllum is absorbed systemically and crosses the placental barrier. It has been associated with the induction of congenital malformations in humans. Routes of exposure: Oral: Easily absorbed even if it induces nausea and vomiting. Dermal: It is absorbed systemically after topical application especially if the skin surface is not intact. Eye: Very well absorbed through mucous membranes. Absorption by route of exposure: Oral absorption: Podophyllum is very well and rapidly absorbed after ingestion. In a fatal case, the patient ingested between 10 and 11 gm of a 25% podophyllum solution in benzoin tincture in the physician's office. He was immediately given syrup of Ipecac and vomited 45 minutes after ingestion. He was also given activated charcoal and magnesium citrate. He died 39 hours after ingestion despite hemoperfusion. Dermal absorption: There are several cases of systemic poisoning following topical application of podophyllum in the literature. In such cases, the onset of symptoms is delayed between two and 24 hours. Distribution by route of exposure: Since podophyllum toxin is water soluble, a small volume of distribution may be predicted. Furthermore, no rebound effects were observed after hemoperfusion. Metabolism: No data available. In a case report, podophyllum toxin in the patient's plasma before, during and after hemoperfusion was examined. A rapid fall in plasma concentration of podophyllum toxin occurred in the period before hemoperfusion was started suggesting rapid metabolism. The delay of onset of symptoms in several case reports may suggest that the metabolized of podophyllum toxin are more toxic than podophyllum toxin itself. This study measured a metabolite during hemoperfusion but several other possible metabolites were found on analysis and removed by hemoperfusion. Mode of action: Toxicodynamics: Podophyllum resin is a potent spindle poison that blocks mitosis metaphase in a manner similar to colchicine. Human poisoning results from either topical application or ingestion of the commercial extract. Overexposure causes neurological, gastrointestinal and hematological toxicity that occasionally results in fatalities. Rarely, poisoning results from consumption of unripe fruit or plant parts and causes primarily diarrhea. The ripe fruit does not produce toxicity. Podophyllum is a keratolytic agent with caustic and cathartic actions. Podophyllum is an antimitotic agent. It binds to tubulin, the protein subunit of the spindle micro-tubules, at the same site or greatly overlapping the same site as colchicine. The antimitotic action of podophyllum toxin probably results from interference with the movement of the chromosomes. The molecular mechanism of mitosis blockade is the disruption of the micro-tubules of the mitotic spindle via binding of podophyllum toxin to tubulin. Podophyllum is caustic but its action differs from those of most caustics in that its effect is neither direct nor immediate: rather, the disruption of cells and erosion of tissue occur slowly subsequent to arrest of cell division and impairment of other cellular processes. Human toxicity: Adults: Most systemic poisoning cases following topical application of podophyllum involved women and some of these were fatal. Serious systemic toxicity has occurred following topical application of podophyllum to large areas or in excessive amounts, or when the medication was allowed to remain in contact with the skin or mucous membranes for a prolonged period of time. The risk of systemic toxicity may be increased when podophyllum is applied to friable bleeding, or recently biopsied warts, or when the medication is inadvertently applied to normal skin or mucous membranes surrounding the affected area. Renal failure and hepatotoxicity (increased serum concentrations of lactate dehydrogenase (LDH), aspartate aminotransferase (AST; SGOT) and alkaline phosphase have occurred following topical application or ingestion of podophyllum. Podophyllum can cause severe systemic toxicity, which may result from topical application and ingestion. The toxic effects are usually reversible but in some instances, they have been fatal. Children: Fever and convulsions seem to be more frequent in children. Most reported cases followed accidental ingestion. Carcinogenicity: Podophyllum is a suspected human carcinogen. Teratogenicity: Podophyllum may be a teratogenic agent in humans. At least two cases of possible teratogenic effects of podophyllum have been described. Interactions: Other keratolytic agents may stimulate dermal absorption of podophyllum. Main adverse effects: The risk of systemic toxicity may be increased when podophyllum is applied to friable, bleeding or recently biopsied warts, or when the medication is inadvertently applied to normal skin or mucous membranes surrounding the affected area. Adverse effects on the nervous system may occur following topical application of podophyllum; these are usually delayed in onset and prolonged in duration. Cerebral toxicity (manifested by altered sensorium ranging from mild confusion to coma) may occur following topical application of podophyllum and continue for 7 to 10 days during which the electorencephalogram (EEG) may show generalized slowing. The following side/adverse effects have been selected on the basis of their potential clinical significance. Skin rash or itching: allergic reaction to benzoin, which may be present in some preparations. Redness, burning or other irritation of the skin has been noted. Abdominal pain, nausea or vomiting. Diarrhea, sometimes severe and prolonged. Clumsiness or unsteadiness. Confusion and reduced reflexes. Excitement, irritability, nervousness and hallucinations. Muscle weakness, leucopenia (sore throat and fever) and thrombocytopenia Autonomic neuropathy (difficult or painful urination; dizziness or lightheadedness, especially when getting from a lying or sitting position; fast heartbeat). Difficulty in breathing. Drowsiness. Paralytic ileus (constipation, nausea and vomiting; pain in upper abdomen or stomach, mild dull and continuing) Peripheral neuropathy (numbness, tingling, pain or weakness in hands or feet). If peripheral neuropathy occurs, it usually appears about 2 weeks after podophyllum application, may worsen progressively for up to 3 months and may persist for up to 9 months or longer. Seizures have been noted. Clinical effects: Acute poisoning: Ingestion: Ingestion may cause: nausea and vomiting, which may be severe and persistent and occur rapidly after ingestion. Abdominal pain, ileus (paralytic), lethargy, coma, tachypnea, respiratory failure, tachycardia, hypotension, cardiac arrhythmia, cardiovascular collapse, oliguria, renal failure, fever, metabolic acidosis, leukocytosis, leucopenia, thrombocytopenia, pancytopenia, peripheral neuropathy, death. Skin exposure: In contrast to ingestion, there will be a delay of up to 24 hours before appearance of signs. These are similar to those occurring after ingestion. Eye contact: Podophyllum may be absorbed through this route but severe systemic poisoning seldom occurs. Local irritation and lesions of cornea and conjunctiva may occur. Chronic poisoning: Ingestion: This type of poisoning occurred when podophyllum was used as a cathartic or slimming aid. It has not been reported in recent years. In such cases, poisoning was sometimes difficult to diagnose since the clinical picture did not resemble that of acute poisoning. The first clinical signs are either hematological, gastro-intestinal or peripheral neuropathy. Skin exposure: Repeated local treatment of warts or condyloma may produce systemic poisoning or local lesions of the skin (erosion, pain, bleeding, infection). Course, prognosis, cause of death: The precise course following overdose is difficult to predict since we seldom have good indicators of the absorbed dose. It should be noted that some severely intoxicated patients (especially children) have survived while others either died or developed permanent sequelae (peripheral neuropathy) with lower doses. Death generally results from the cerebral; cardiovascular; renal; or hematological complications. Systematic description of clinical effects: Cardiovascular: Tachycardia, cardiac, arrhythmias, hypotension and cardiovascular collapse. Respiratory: Tachypnea and respiratory failure. Pneumonitis (resembling chemical pneumonitis) and pulmonary edema (rarely). Neurological: Central Nervous System (CNS): Confusion, lethargy, coma and convulsions. Peripheral nervous system: Peripheral neuropathy which develops over several days and may take weeks or months to regress. There may be permanent sequelae. Autonomic nervous system: Paralytic ileus. Skeletal and smooth muscle: Rhabdomyolysis may occur with myoglobinuria. This may aggravate the renal failure. Phosphokinase (CPK) should be monitored. Gastrointestinal: Nausea and vomiting which may be persistent and severe; abdominal pain; paralytic ileus and diarrhea which may produce water and electrolyte imbalance. Hepatic: Elevation of hepatic enzymes. Urinary: Renal: Oliguria and renal insufficiency. Other: Cystitis and painful micturition. Endocrine and reproductive system: Fetal death, abortion, premature labor and fetal malformations. Dermatologic: Pruritus around the treated sites especially if the skin has not been protected by petroleum jelly. Irritation, urticaria, skin necrosis and bleeding. Scarring of tissue, especially of anogenital regions, paraphimosis that may require circumcision and pseudo epitheliomatosis hyperplasia. Eye, ear, nose, throat: local effects: Irritation of skin or mucous membrane, necrosis, scarring of tissues, bleeding and corneal erosion. Hematological: Leucocytosis followed by leucopenia, anemia, thrombocytopenia and pancytopenia. Special risks: The use of podophyllum is contraindicated in pregnant or lactating women. ANIMAL STUDIES: Mutagenicity: Podophyllum is mutagenic in Salmonella typhimurium. /Podophyllum/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

依托泊苷，是一种半合成的足叶草毒素衍生物，通过抑制拓扑异构酶II来诱导DNA断裂。该药物在细胞周期的晚S期和早G2期最为活跃。替尼泊苷是一种具有非常相似药理特性的类似物。足叶草毒素衍生物在晚S期和早G2期显示出对拓扑异构酶II的绑定活性。例如，依托泊苷可以绑定并稳定由该酶引起的临时断裂，破坏断裂的修复过程，从而阻止双链DNA的通过，最终停止DNA的解旋和复制。已经在中国仓鼠细胞中描述了足叶草毒素、或者其拓扑异构酶II抑制衍生物如依托泊苷（VP-16）的耐药突变体。这些突变体的相互排斥的交叉耐药模式提供了一个高度特异性的手段来区分这两种足叶草毒素衍生物。对足叶草毒素耐药的中国仓鼠细胞受到了一个后来被识别为哺乳动物HSP60或伴侣蛋白的P1蛋白的影响。（维基百科）

Etoposide, a semisynthetic derivative of podofilox, induces DNA breakage through its inhibition of topoisomerase II. The drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an analog with very similar pharmacologic characteristics. Podofilox derivatives display binding activity to the enzyme topoisomerase II during the late S and early G2 stage. For instance, etoposide binds and stabilizes the temporary break caused by the enzyme, disrupts the reparation of the break through which the double-stranded DNA passes, and consequently stops DNA unwinding and replication. Mutants resistant to either podofilox, or to its topoisomerase II inhibitory derivatives such as etoposide (VP-16), have been described in Chinese hamster cells. The mutually exclusive cross-resistance patterns of these mutants provide a highly specific mean to distinguish the two kinds of podofilox derivatives. Mutant Chinese hamster cells resistant to podofilox are affected in a protein P1 that was later identified as the mammalian HSP60 or chaperonin protein. (Wikipedia)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类无致癌性（未列入国际癌症研究机构IARC清单）。

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

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

将0.05毫升0.5%足叶草毒素溶液涂抹在外阴部不会导致可检测的血清水平。涂抹0.1到1.5毫升后，涂抹后一至两小时内的血清水平峰值达到1至17纳克/毫升。

Topical application of 0.05 mL of 0.5% podofilox solution to external genitalia did not result in detectable serum levels. Applications of 0.1 to 1.5 mL resulted in peak serum levels of 1 to 17 ng/mL one to two hours after application.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 解毒与急救

治疗全身毒性或意外摄入主要是支持性的。为了减少吸收：清洗皮肤上残留的药物。支持性护理：已知或疑似故意过量服用的患者应转诊进行精神科咨询。

Treatment of systemic toxicity or accidental ingestion is essentially supportive. To decrease absorption: Wash the skin free of any remaining drug. Supportive care: Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

外阴部涂抹0.05毫升0.5%足叶草毒素溶液后，未检测到可检测的血清水平。涂抹0.1至1.5毫升后，血清水平在涂抹后一至两小时达到峰值，为1至17纳克/毫升。

Topical application of 0.05 mL of 0.5% podofilox solution to external genitalia did not result in detectable serum levels. Applications of 0.1 to 1.5 mL resulted in peak serum levels of 1 to 17 ng/mL one to two hours after application.

来源:DrugBank

吸收、分配和排泄

小量足叶草毒素可能会在局部应用后被系统吸收。在一项针对由人类乳头瘤病毒引起的外生殖器疣成年患者的研究中，将0.05毫升0.5%足叶草毒素溶液应用于外生殖器并未导致可检测的血清药物浓度；然而，局部应用0.1-1.5毫升的溶液后，在涂抹后1-2小时达到了1-17纳克/毫升的血清峰值浓度。

Small amounts of podofilox may be absorbed systemically following topical application. In a study in adults with anogenital warts caused by human papillomavirus, topical application of 0.05 mL of podofilox 0.5% solution to external genitalia did not result in detectable serum concentrations of the drug; however, topical application of 0.1-1.5mL of the solution resulted in peak serum concentrations of 1-17 ng/mL at 1-2 hours aft