乌头碱

烏頭鹼（）是一種生物鹼毒素。是常用中藥烏頭屬中所含有的一種化學物質，具強烈毒性，口服0.2mg左右即能使人中毒，3-5mg即可致死。民间常用草乌、川乌等植物来泡制药酒，但这种药酒可能是极端危险的，也经常因此出现中毒甚至死亡的情况。

 用途 
烏頭鹼以前被用作解熱藥和鎮痛藥，但在草藥中的應用仍然有限。狹窄的治療指數使計算合適的劑量很困難。

 結構和反應性 
附子屬和翠雀屬植物的生物活性分離物被歸類為去甲二萜生物碱。在生物遺傳學，烏頭鹼不是真正的生物鹼，因為並非來源於氨基酸。烏頭鹼最終來源於異戊二烯，因此它在技術上是一種萜類化合物和偽生物鹼。根據C18碳的存在與否進一步細分。烏頭鹼是一種C19去甲二萜生物碱，因為它含有C18。烏頭鹼幾乎不溶於水，但極易溶於有機溶劑，例如氯仿或乙醚。如果酒精濃度足夠高，烏頭鹼也可溶於乙醇和水的混合物中。

像許多其他生物鹼一樣，烏頭鹼六元環的鹼性氮很容易形成鹽和離子，使其對極性和親脂性結構過血腦屏障。
在甲醇中加熱烏頭鹼，c8位的乙醯氧基很容易被甲氧基取代，產生8-去乙醯基-8-O-甲基衍生物。如果將乾燥的烏頭鹼加熱，它會發生熱解反應產生焦烏頭鹼((1α,3α,6α,14α,16β)-20-ethyl-3,13-dihydroxy-1,6,16-trimethoxy-4-(methoxymethyl)-15-oxoaconitan-14-yl benzoate)，化學式C32H43NO9。

 毒性 
烏頭鹼的毒性作用已在多種動物身上進行了測試有效，包括哺乳動物（狗、貓、豚鼠、小鼠、大鼠和兔子）、鴿、青蛙。觀察到的毒性作用有：局部麻醉、腹瀉、抽搐、心律失常、死亡。

根據對人類附子中毒的不同報導的回顧，觀察到以下臨床特徵：

 神經系統：感覺異常和臉、口周區域和四肢麻木、肌肉無力。
 心血管：低血壓、心悸、胸痛、心動過緩、、室性異位及其他心律失常、室性心律失常、
 胃腸道：噁心、嘔吐、腹痛、腹瀉
 其他：頭暈、過度換氣、出汗、呼吸困難、意識模糊、頭痛、流淚

烏頭鹼中毒的最初症狀出現在口服後約20分鐘至2小時，包括感覺異常、出汗、噁心。這會導致嚴重的嘔吐、絞痛性腹瀉、劇烈疼痛，然後骨骼肌麻痺。威脅生命的心律失常，包括室性心動過速、心室顫動，會因呼吸麻痺或心臟驟停而死亡。

小鼠的值為口服 1 mg/kg、靜脈 0.100 mg/kg、腹膜 0.270 mg/kg 和皮下 0.270 mg/kg。小鼠的最低致死量（）為口服 1 mg/kg 和腹腔 0.100 mg/kg。小鼠的最低中毒量（）為 0.0549 mg/kg 皮下注射。大鼠靜脈注射的值為 0.064 mg/kg。大鼠的為靜脈注射 0.040 mg/kg和腹腔 0.250 mg/kg。大鼠的腸胃為 0.040 mg/kg。有關更多參見下表：表示平均致死量；是指最低致死量；表示最低中毒量。

 物種  測試  路線  劑量（mg/kg）  毒性 人類    口服  0.028  行為：興奮
胃腸道：運動亢進、腹瀉、其他變化 人類    口服  0.029  除致死劑量值外未報告詳情毒性作用 貓    靜脈  0.080  行為：抽搐或對癲癇發作閾值的影響  貓  LDLo 皮下  0.100  除致死劑量值外未報告詳情毒性作用 豚鼠    靜脈  0.060 行為：抽搐或對癲癇發作閾值的影響  豚鼠    皮下  0.050  除致死劑量值外未報告詳情毒性作用 豚鼠    靜脈  0.025  心臟：心律失常（包括傳導改變）  小鼠    腹腔  0.270  除致死劑量值外未報告詳情毒性作用 小鼠    靜脈  0.100  感覺器官和特殊感覺（眼睛）：流淚
行為：抽搐或對癲癇發作閾值的影響
肺、胸：呼吸困難 小鼠    口服  1  除致死劑量值外未報告詳情毒性作用 小鼠    皮下  0.270 除致死劑量值外未報告詳情毒性作用 小鼠    腹腔  0.100  除致死劑量值外未報告詳情毒性作用 小鼠    口服  1  行為：抽搐或對癲癇發作閾值的影響
心臟：心律失常（包括傳導改變）
胃腸道：運動亢進、腹瀉 小鼠    皮下  0.0549  周圍神經和感覺：局部麻醉
行為：鎮痛 兔子    皮下  0.131  除致死劑量值外未報告詳情毒性作用 大鼠    靜脈  0.080  行為：抽搐或對癲癇發作閾值的影響  大鼠    靜脈  0.064  除致死劑量值外未報告詳情毒性作用 大鼠    腹腔  0.250  心臟：其他變化
肺、胸：呼吸困難 大鼠    靜脈  0.040  心臟：心律失常（包括傳導改變）  大鼠    腸外  0.040  心臟：心律失常（包括傳導改變）  青蛙    皮下  0.586  除致死劑量值外未報告詳情毒性作用 鴿子    皮下  0.066  除致死劑量值外未報告詳情毒性作用

對於人類，1969 年報導的最低口服致死劑量為 28 μg/kg。

乌头碱（草乌、川乌）中毒在急诊及内科中常见，多因服用自制中药及自制药膳不当所致。

它主要使迷走神经兴奋，对周围神经损害临床主要表现为口舌及四肢麻木，全身紧束感等，通过兴奋迷走神经而降低窦房结的自律性，引起異位起搏点的自律性增高而引起各心律失常，损害心肌。

 診斷和治療 
為了分析血液、血清和尿液等生物樣本中的「烏頭屬」生物鹼，已有數種氣相色譜法-質譜聯用（GC-MS）方法被描述。這些方法採用多種萃取過程，然後衍生化為三甲基矽基衍生物。此外，也開發了新且靈敏的液相色譜法-質譜聯用（HPLC-MS）方法，通常會先將樣品進行固相萃取（SPE）純化。抗心律不整藥物利多卡因可有效治療烏頭鹼中毒患者。因為烏頭鹼是鈉離子通道受體的促效劑，阻斷鈉通道的抗心律不整藥物（Vaughan-Williams I類）可能是治療烏頭鹼誘發心律不整的首選藥物。動物實驗表明，河豚毒素可以降低烏頭鹼的死亡率。烏頭鹼的毒性作用被河豚毒素減弱，可能是兩者對興奮性膜（excitable membranes）的相互拮抗作用所致。此外在動物試驗中，似乎對烏頭鹼的急性毒性具有解毒作用。可能是烏頭鹼和芍藥苷之間的藥物動力學相互作用，導致動物體內烏頭鹼的藥物動力學行為改變所致。如果在緊急情況下，可以使用鞣酸或木炭粉清洗胃部。在獲得專業幫助之前，服用一些心臟興奮劑（例如濃縮咖啡或咖啡因）也可能有所幫助。

 作用 

Aconitine can interact with the voltage-dependent sodium-ion channels, which are proteins in the cell membranes of excitable tissues, such as cardiac and skeletal muscles and neurons. These proteins are highly selective for sodium ions. They open very quickly to depolarize the cell membrane potential, causing the upstroke of an action potential. Normally, the sodium channels close very rapidly, but the depolarization of the membrane potential causes the opening (activation) of potassium channels and potassium efflux, which results in repolarization of the membrane potential.

Aconitine binds to the channel at the neurotoxin binding site 2 on the alpha subunit.This binding results in a sodium-ion channel that stays open longer. Aconitine suppresses the conformational change in the sodium-ion channel from the active state to the inactive state. The membrane stays depolarized due to the constant sodium influx (which is 10–1000-fold greater than the potassium efflux). As a result, the membrane cannot be repolarized. The binding of aconitine to the channel also leads to the channel to change conformation from the inactive state to the active state at a more negative voltage.In neurons, aconitine increases the permeability of the membrane for sodium ions, resulting in a huge sodium influx in the axon terminal. As a result, the membrane depolarizes rapidly. Due to the strong depolarization, the permeability of the membrane for potassium ions increases rapidly, resulting in a potassium reflux to release the positive charge out of the cell. Not only the permeability for potassium ions but also the permeability for calcium ions increases as a result of the depolarization of the membrane. A calcium influx takes place. The increase of the calcium concentration in the cell stimulates the release of the neurotransmitter acetylcholine into the synaptic cleft. Acetylcholine binds to acetylcholine receptors at the postsynaptic membrane to open the sodium-channels there, generating a new action potential.

Research with mouse nerve-hemidiaphragm muscle preparation indicate that at low concentrations (<0.1 μM) aconitine increases the electrically evoked acetylcholine release causing an induced muscle tension.Action potentials are generated more often at this concentration. At higher concentration (0.3–3 μM) aconitine decreases the electrically evoked acetylcholine release, resulting in a decrease in muscle tension. At high concentration (0.3–3 μM), the sodium-ion channels are constantly activated, transmission of action potentials is suppressed, leading to non-excitable target cells or paralysis.

 合成 

Aconitine is biosynthesized by the monkshood plant via the terpenoid biosynthesis pathway (MEP chloroplast pathway).Approximately 700 naturally occurring C19-diterpenoid alkaloids have been isolated and identified, but the biosynthesis of only a few of these alkaloids are well understood.

Likewise, only a few alkaloids of the aconitine family have been synthesized in the laboratory.  In particular, despite over one hundred years having elapsed since its isolation, the prototypical member of its family of norditerpenoid alkaloids, aconitine itself, represents a rare example of a well-known natural product that has yet to succumb to efforts towards its total synthesis.  The challenge that aconitine poses to synthetic organic chemists is due to both the intricate interlocking hexacyclic ring system that make up its core and the elaborate collection of oxygenated functional groups at its periphery.  A handful of simpler members of the aconitine alkaloids, however, have been prepared synthetically.  In 1971, the Weisner group discovered the total synthesis of talatisamine (a C19-norditerpenoid).In the subsequent years, they also discovered the total syntheses of other C19-norditerpenoids, such as chasmanine,and 13-deoxydelphonine.


The total synthesis of napelline (Scheme a) begins with aldehyde 100.In a 7 step process, the A-ring of napelline is formed (104). It takes another 10 steps to form the lactone ring in the pentacyclic structure of napelline (106). An additional 9 steps creates the enone-aldehyde 107. Heating in methanol with potassium hydroxide causes an aldol condensation to close the sixth and final ring in napelline (14). Oxidation then gives rise to diketone 108 which was converted to (±)-napelline (14) in 10 steps.

A similar process is demonstrated in Wiesner's synthesis of 13-desoxydelphinone (Scheme c).The first step of this synthesis is the generation of a conjugated dienone 112 from 111 in 4 steps. This is followed by the addition of a benzyl vinyl ether to produce 113. In 11 steps, this compound is converted to ketal 114. The addition of heat, DMSO and o-xylene rearranges this ketol (115), and after 5 more steps (±)-13-desoxydelphinone (15) is formed.

Lastly, talatisamine (Scheme d) is synthesized from diene 116 and nitrile 117.The first step is to form tricycle 118  in 16 steps. After another 6 steps, this compound is converted to enone 120. Subsequently, this allene is added to produce photoadduct 121. This adduct group is cleaved and rearrangement gives rise to the compound 122. In 7 steps, this compound forms 123, which is then rearranged, in a similar manner to compound 114, to form the aconitine-like skeleton in 124. A racemic relay synthesis is completed to produce talatisamine (13).

More recently, the laboratory of the late David Y. Gin completed the total syntheses of the aconitine alkaloids nominineand neofinaconitine.

 代謝 

Aconitine is metabolized by cytochrome P450 isozymes (CYPs). There has been research in 2011 in China to investigate in-depth the CYPs involved in aconitine metabolism in human liver microsomes.It has been estimated that more than 90 percent  of currently available human drug metabolism can be attributed to eight main enzymes (CYP 1A2, 2C9, 2C8, 2C19, 2D6, 2E1, 3A4, 3A5).The researchers used recombinants of these eight different CYPs and incubated it with aconitine. To initiate the metabolism pathway the presence of NADPH was needed. Six CYP-mediated metabolites (M1–M6) were found by liquid chromatography, these six metabolites were characterized by mass-spectrometry. The six metabolites and the involved enzymes are summarized in the following table:

 Metabolite Name  Involved CYPs M1  O-Demethyl-aconitine  CYP3A4, CYP3A5, CYP2D6, CYP2C8 M2  16-O-Demethyl-aconitine  CYP3A4, CYP3A5, CYP2D6, CYP2C9 M3  N-deethyl-aconitine  CYP3A4, CYP3A5, CYP2D6, CYP2C9 M4  O-didemethyl-aconitine  CYP3A5, CYP2D6 M5  3-Dehydrogen-aconitine  CYP3A4, CYP3A5 M6  Hydroxyl-aconitine  CYP3A5, CYP2D6

Selective inhibitors were used to determine the involved CYPs in the aconitine metabolism. The results indicate that aconitine was mainly metabolized by CYP3A4, 3A5 and 2D6. CYP2C8 and 2C9 had a minor role to the aconitine metabolism, whereas CYP1A2, 2E1 and 2C19 did not produce any aconitine metabolites at all. The proposed metabolic pathways of aconitine in human liver microsomes and the CYPs involved to it are summarized in the table above.

 著名中毒事件 

During the Indian Rebellion of 1857, a British detachment was the target of attempted poisoning with aconitine by the Indian regimental cooks. The plot was thwarted by John Nicholson who, having detected the plot, interrupted the British officers just as they were about to consume the poisoned meal. The chefs refused to taste their own preparation, whereupon it was force-fed to a monkey who "expired on the spot". The cooks were hanged.

Aconitine was the poison used by George Henry Lamson in 1881 to murder his brother-in-law in order to secure an inheritance. Lamson had learned about aconitine as a medical student from professor Robert Christison, who had taught that it was undetectable—but forensic science had improved since Lamson's student days.

Rufus T. Bush, American industrialist and yachtsman, died on September 15, 1890, after accidentally taking a fatal dose of aconite.

In 1953 aconitine was used by a Soviet biochemist and poison developer, Grigory Mairanovsky, in experiments with prisoners in the secret NKVD laboratory in Moscow. He admitted killing around 10 people using the poison.

In 2004 Canadian actor Andre Noble died from aconitine poisoning. He accidentally ate some monkshood while he was on a hike with his aunt in Newfoundland.

In 2009 Lakhvir Singh of Feltham, west London, used aconitine to poison the food of her ex-lover Lakhvinder Cheema (who died as a result of the poisoning) and his current fiancée Aunkar Singh. Singh received a life sentence with a 23-year minimum for the murder on February 10, 2010.

 流行文化 

烏頭鹼是古代世界最受歡迎的毒藥。普布利烏斯·奧維修斯·納索提到了眾所周知的繼母不喜歡繼子的問題，他寫道：

Lurida terribiles miscent aconita novercae.Ovid, Metamorphoses, 1.147

Fearsome stepmothers mix lurid aconites. 

Aconitine was also made famous by its use in Oscar Wilde's 1891 story "Lord Arthur Savile's Crime".  Aconite also plays a prominent role in James Joyce's Ulysses, in which the father to protagonist Leopold Bloom used pastilles of the chemical to commit suicide.  Aconitine poisoning plays a key role in the murder mystery Breakdown by Jonathan Kellerman (2016). In Twin Peaks (season 3) Part 13, aconitine is suggested to poison the main character.

Monk's Hood is the name of the third Cadfael Novel written in 1980 by Ellis Peters. The novel was made into an episode of the well known television series Cadfael starring Derek Jacobi.

 临床作用 

 参考文献 

 外部連結 
 烏頭堿 Aconitine 中草藥化學圖像數據庫 (香港浸會大學中醫藥學院) 
 乌头碱 aconitine 化学空间 Chem-Station 

Category:生物碱
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Category:叔醇