5-hydroxytryptophan (5-HTP)   中文名称: DL-5-羟基色氨酸

Endogenous Metabolite

L-5-羟色氨酸（5-HTP）是一种药物，也是一些膳食补充剂的天然成分。5-HTP由色氨酸通过色氨酸羟化酶（TPH）产生，其存在于两种异构体（TPH1和TPH2）中。5-HTP的脱羧作用产生血清素（5-羟色胺，5-HT），其进一步转化为褪黑素（N-乙酰基-5-甲氧基色胺）。5-HTP在神经和代谢疾病中起着重要作用，其由色氨酸合成是血清素和褪黑素生物合成的限制步骤。在这篇综述中，在了解了5-羟色胺的主要天然来源后，将描述分子工程对5-羟色胺的化学分析和合成、生物合成以及微生物生产。5-HTP的生理作用在动物研究和人体临床试验中都有讨论。还讨论了5-HTP在治疗抑郁、焦虑、恐慌、睡眠障碍、肥胖、肌阵挛和血清素综合征中的生理作用。还讨论了5-羟色胺的毒性以及色氨酸和5-羟色胺制剂中存在的有毒杂质的出现。[2]

5-羟色胺前体5-羟基-L-色氨酸（5-HTP）剂量依赖性地（30-100mg/kg腹腔注射）增加雄性大鼠的血浆泌乳素和促肾上腺皮质激素。催乳素和促肾上腺皮质激素对5-HTP（100 mg/kg）的反应通过用非选择性5-HT受体拮抗剂美特戈林（0.5 mg/kg）和选择性5-HT2受体拮抗剂利坦色林（0.4 mg/kg）、酮色林（2.5 mg/kg）、ICI（5.0 mg/kg）和司匹酮（1.0 mg/kg）预处理而减弱。5-HT1受体拮抗剂普萘洛尔（40 mg/kg）和品多醇（4.0 mg/kg）不能拮抗催乳素和促肾上腺皮质激素对5-HTP（100 mg/kg）的反应，选择性5-HT3受体拮抗剂BRL 43694（1.0 mg/kg）也是如此。结果表明，雄性大鼠对5-HTP的催乳素和促肾上腺皮质激素反应是由5-HT2受体介导的。[1]

Serotonin has a facilitatory role in the role of prolactin and adrenocorticotropin (ACTH) secretion. The serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) dose dependently (30-100 mg/kg i.p.) increased plasma prolactin and ACTH in the male rat. Prolactin and ACTH responses to 5-HTP (100 mg/kg) were attenuated by pretreatment with the non-selective 5-HT receptor antagonist, metergoline (0.5 mg/kg), and by the selective 5-HT2 receptor antagonists, ritanserin (0.4 mg/kg), ketanserin (2.5 mg/kg), ICI (5.0 mg/kg) and spiperone (1.0 mg/kg). The 5-HT1 receptor antagonists, propranolol (40 mg/kg) and pindolol (4.0 mg/kg), failed to antagonize the prolactin and ACTH responses to 5-HTP (100 mg/kg), as did the selective 5-HT3 receptor antagonist, BRL 43694 (1.0 mg/kg). The results suggest that the prolactin and ACTH responses to 5-HTP in the male rat are mediated by 5-HT2 receptors. [1]

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Single-dose administration of 5-hydroxytryptophan (5-HTP) is regularly used as a challenge test of the serotonergic system. The use of 5-HTP has been limited by an apparent small window between the occurrence of neuroendocrine endpoints and the occurrence of side effects. Therefore, many dosing strategies have been tried with and without concurrent administration of carbidopa, a peripheral inhibitor of the decarboxylation from 5-HTP to serotonin. The aim of the current study was to assess the relation between pharmacokinetics and pharmacodynamics of 5-HTP. Twelve healthy male volunteers were included in a placebo-controlled, randomized, four-way crossover, double-blind, single-dose investigation of oral 5-HTP with or without coadministration of carbidopa. The four dose regimens were placebo, 5-HTP 100 mg, 5-HTP 200 mg, and 5-HTP 100 mg with coadministration of carbidopa 100 mg and 50 mg at 3 hours before and 3 hours after the administration of 5-HTP, respectively. The last regimen resulted in a doubling of the elimination half-life, an apparent clearance at least 14 times smaller, and a 15.4 times greater area under the curve compared with 5-HTP 100 mg without carbidopa. Furthermore, it was the only regimen to induce a significant change in cortisol and prolactin. It did not induce any change in subjective psychologic symptoms or cardiovascular parameters, but it was the only regimen to induce some nausea in three participants. The authors conclude that this regimen of 5-HTP 100 mg plus carbidopa is a relatively simple, effective, and tolerable challenge of the presynaptic serotonergic system. Further increase of the dose of 5-HTP might improve the size of the effect on endpoints as long as the tolerability remains good. [2]

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Previous research showed that lowering the availability of serotonin to the brain by tryptophan depletion increases the vulnerability of panic disorder patients for an experimental 35% CO(2) panic challenge. The results also suggested that increased availability of serotonin inhibits the response to such a challenge. In the present study, this latter possibility is examined. The reaction of 24 panic disorder patients and 24 healthy volunteers to a 35% CO(2) panic challenge was assessed following administration of 200-mg L-5-hydroxytryptophan (the immediate precursor of serotonin) or placebo. L-5-Hydroxytryptophan significantly reduced the reaction to the panic challenge in panic disorder patients, regarding subjective anxiety, panic symptom score and number of panic attacks, as opposed to placebo. No such effect was observed in the healthy volunteers. L-5-Hydroxytryptophan acts to inhibit panic, which supports a modulatory role of serotonin in panic disorder.[3]

Absorption, Distribution and Excretion
The immediate precursor in the serotonin synthetic route, 5-hydroxytryptophan (5-HTP), labeled with 11C in the beta position, has become available for studies using positron emission tomography (PET) to examine serotonin formation in human brain. Normalized uptake and intracerebral utilization of tracer amounts of (beta-11C)5-HTP were studied twice in six healthy male volunteers, three of them before and after pharmacological pretreatments ... Pretreatments with benserazide, p-chlorophenylalanine (PCPA), and unlabeled 5-HTP all significantly increased uptake of (beta-11C)5-HTP. The utilization rates in both striatal and frontal cortex were higher than those in the surrounding brain, indicating that PET studies using (beta-11C)5-HTP as a ligand quantitate selective processes in the utilization of 5-HTP.
The efficiency of absorption of 5HTP, as well as its decarboxylation product serotonin, is approximately 47% to 84%. Absorption of 5-HTP occurs by an active transport process. 5-HTP is transported by the portal circulation to the liver where approximately 25% of an administered dose is metabolized ... . 5-HTP that is not metabolized in the liver is transported by the general circulation to the various tissues of the body, including the brain. 5-HTP readily crosses the blood-brain barrier, and is converted to serotonin in brain cells.

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Metabolism / Metabolites
5-HTP is transported by the portal circulation to the liver where approximately 25% of an administered dose is metabolized via vitamin B6-dependent L-aromatic amino acid decarboxylase to 5-hydroxytryptamine (5-HT) /serotonin/. 5-HT is subsequently metabolized to 5-hydroxyindole acetaldehyde which is rapidly metabolized to 5-hydroxyindole acetaldehyde which is rapidly metabolized to 5-hydroxyindoleacetic acid (5-HIAA).
5-Hydroxytryptophan is decarboxylated to serotonin (5-hydroxytryptamine or 5-HT) by the enzyme aromatic-L-amino-acid decarboxylase with the help of vitamin B6. This reaction occurs both in nervous tissue and in the liver.

Toxicity Summary
5-Hydroxy-L-tryptophan is the immediate precursor of the neurotransmitter serotonin. An accumulation of 5-hydroxy-L-tryptophan in cerebrospinal fluid occurs in aromatic L-amino acid decarboxylase deficiency, accompanied by an increased excretion in the urine of the patients, which are indicative of the disorder. 5-Hydroxy-L-tryptophan easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. Supplementation with 5-hydroxy-L-tryptophan is hypothesized to normalize serotonin synthesis, which is putatively related to its antidepressant properties.

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Toxicity Summary
5-Hydroxy-L-tryptophan is the immediate precursor of the neurotransmitter serotonin. An accumulation of 5-hydroxy-L-tryptophan in cerebrospinal fluid occurs in aromatic L-amino acid decarboxylase deficiency, accompanied by an increased excretion in the urine of the patients, which are indicative of the disorder. 5-Hydroxy-L-tryptophan easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. Supplementation with 5-hydroxy-L-tryptophan is hypothesized to normalize serotonin synthesis, which is putatively related to its antidepressant properties.

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Health Effects
Chronically high levels of 5-hydroxytryptophan are associated with Aromatic L-Amino acid Decarboxylase Deficiency.

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Interactions
5-HTP may decrease the effectiveness of methylsergide and cyproheptadine.

DURATION OF /SRP:CNS DEPRESSION/ INDUCED BY ETHANOL (3.0 G/KG, IP) IN MICE OF BOTH SEXES WAS INCR BY PRETREATMENT WITH 5-HYDROXYTRYPTOPHAN (60 MG/KG, IP).

Concurrent use of 5-HTP with a selective serotonin reuptake inhibitors (SSRI) /citalopram, fluvoxamine maleate, fluoxetine, paroxetine, sertraline, venlafaxine/ may potentiate the antidepressant effect of the SSRI and may also increase the risk of adverse reactions.

Phenoxybenzamine inhibits the conversion of 5-HTP to serotonin.

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Antidote and Emergency Treatment
VET: Treatment consists of early decontamination, control of CNS signs (diazepam, barbiturates), thermoregulation (cool water both, fans), fluid therapy, and administration of a serotonin antagonist such as cyproheptadine ... .

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mouse LD50 intraperitoneal 200 mg/kg National Technical Information Service., AD277-689
mouse LD50 oral >6 gm/kg Nippon Yakurigaku Zasshi. Japanese Journal of Pharmacology., 69(523), 1973 [PMID:4546003]
mouse LD50 intraperitoneal 1080 mg/kg Nippon Yakurigaku Zasshi. Japanese Journal of Pharmacology., 69(523), 1973 [PMID:4546003]
mouse LD50 intravenous >400 mg/kg Nippon Yakurigaku Zasshi. Japanese Journal of Pharmacology., 69(523), 1973 [PMID:4546003]

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Interactions
5-HTP may decrease the effectiveness of methylsergide and cyproheptadine.
DURATION OF /SRP:CNS DEPRESSION/ INDUCED BY ETHANOL (3.0 G/KG, IP) IN MICE OF BOTH SEXES WAS INCR BY PRETREATMENT WITH 5-HYDROXYTRYPTOPHAN (60 MG/KG, IP).
Concurrent use of 5-HTP with a selective serotonin reuptake inhibitors (SSRI) /citalopram, fluvoxamine maleate, fluoxetine, paroxetine, sertraline, venlafaxine/ may potentiate the antidepressant effect of the SSRI and may also increase the risk of adverse reactions.
Phenoxybenzamine inhibits the conversion of 5-HTP to serotonin.
For more Interactions (Complete) data for 5-HYDROXYTRYPTOPHAN (16 total), please visit the HSDB record page.

[1]. Mediation of ACTH and prolactin responses to 5-HTP by 5-HT2 receptors. Eur J Pharmacol. 1990 Apr 10;179(1-2):103-9.

[2]. Placebo-controlled comparison of three dose-regimens of 5-hydroxytryptophan challenge test in healthy volunteers. J Clin Psychopharmacol. 2002 Apr;22(2):183-9.

[3]. Acute L-5-hydroxytryptophan administration inhibits carbon dioxide-induced panic in panic disorder patients. Psychiatry Res. 2002 Dec 30;113(3):237-43.

Therapeutic Uses
5-HTP has shown some usefulness in some conditions characterized, in part, by serotonin deficits, principally depression. It has also been shown to be useful in some with obesity, insomnia, fibromyalgia and chronic tension headache.
It has been long known that brain serotonin systems contribute to the modulation of food intake and satiety. An increase of intrasynaptic serotonin tends to reduce food consumption. Thus, one might consider that individuals taking 5-HTP might experience increase satiety and weight loss over a period of time. There are few studies on the effects of 5-HTP on obesity and they suggest an anorectic effect of 5-HTP.
There is some evidence that 5-HTP ... can improve postural equilibrium, dysarthria in patients with various inherited and acquired cerebellar ataxias, and particularly in those with lesions located precisely in the anterior lobe vermis. Improvements in coordination have been reported in patients with Friedreich"s ataxia; however, the effect is only partial and not clinically major.
Exptl Ther: Rats of the Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) strains were placed on a 4% NaCl diet and blood pressures were monitored. Chronic subcutaneous infusion L-5-hydroxytryptophan (L-5-HTP, 12.6 mg/day) by osmotic minipumps significantly decreased the elevated systolic blood pressure of DS rats on a 4% NaCl diet. Blood pressures of DR rats were unaffected by treatment with L-5-HTP. Cardiac hypertrophy was associated with Dahl salt-induced hypertension. However, treatment with L-5-HTP failed to reduce the weight of the heart significantly. These results suggest that chronic administration of L-5-HTP was effective in reducing the elevated blood pressure in the DS model. The specific mechanisms by which L-5-HTP reduces the elevated blood pressure in DS rats is not clear and remains for further study.
For more Therapeutic Uses (Complete) data for 5-HYDROXYTRYPTOPHAN (6 total), please visit the HSDB record page.

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Drug Warnings
Other reported side effects, include nausea, diarrhea, loss of appetite, vomiting and difficult breathing. Neurological side effects, including dilation of the pupils, abnormally sensitive reflexes, loss of muscle coordination and blurring of vision, have been reported in those taking large doses of 5-HTP. Cardiac dysrhythmias have also been reported.
Eosinophilia and eosinophilia-myalgia syndrome (EMS) have been reported in those taking 5-HTP. The eosinophilia myalgia syndrome is similar to that caused by L-tryptophan and was linked to contaminants in the 5-HTP preparation, rather than 5-HTP itself. Changing the 5-HTP lot in one group of patients resolved the eosinophilia. A scleroderma-like skin condition has been reported in some taking a combination of 5-HTP and carbidopa.
5-HTP should be avoided by pregnant women and nursing mothers.
5-HTP should be avoided by those with ischemic heart disease (history of myocardial infarction, angina pectoris, documented silent ischemia), coronary artery spasm (e.g., Prinzmetal's angina), uncontrollable hypertension and any other significant cardiovascular disease.
For more Drug Warnings (Complete) data for 5-HYDROXYTRYPTOPHAN (8 total), please visit the HSDB record page.

C11H12N2O3

220.23

220.084

56-69-9

144

White to off-white solid

1.5±0.1 g/cm3

520.6±50.0 °C at 760 mmHg

298-300ºC

268.7±30.1 °C

0.0±1.4 mmHg at 25°C

1.737

-0.14

99.34

4

4

3

16

272

0

O([H])C1C([H])=C([H])C2=C(C=1[H])C(=C([H])N2[H])C([H])([H])C([H])(C(=O)O[H])N([H])[H]

LDCYZAJDBXYCGN-UHFFFAOYSA-N

InChI=1S/C11H12N2O3/c12-9(11(15)16)3-6-5-13-10-2-1-7(14)4-8(6)10/h1-2,4-5,9,13-14H,3,12H2,(H,15,16)

2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid; 5-hydroxy-DL-tryptophan

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.08 mg/mL (9.45 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (9.45 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: 2.08 mg/mL (9.45 mM) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: ≥ 2.0 mg/mL (9.4 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + + 45% Saline
≥ 2.0 mg/mL (9.4 mM) in 10% DMSO + 90% (20% SBE-β-CD in saline)
≥ 2.0 mg/mL (9.4 mM) in 10% DMSO + 90% Corn oil
5.8 mg/mL (26.0 mM) in PBS, 澄清溶液
20 mg/mL (90.8 mM) in 0.5% CMC-Na/saline water, suspension

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配方 5 中的溶解度: 5.88 mg/mL (26.70 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶 (<60°C).

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配方 6 中的溶解度: 20 mg/mL (90.82 mM) in 0.5% CMC-Na/saline water (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
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