Paclitaxel (PTX), sold under the brand name Taxol among others, is a
chemotherapy medication used to treat a number of types of cancer.
This includes ovarian cancer, breast cancer, lung cancer, Kaposi
sarcoma, cervical cancer, and pancreatic cancer. It is given by
injection into a vein. There is also an albumin bound
Common side effects include hair loss, bone marrow suppression,
numbness, allergic reactions, muscle pains, and diarrhea. Other
serious side effects include heart problems, increased risk of
infection, and lung inflammation. There are concerns that use
during pregnancy may cause birth defects.
Paclitaxel is in the
taxane family of medications. It works by interference with the
normal function of microtubules during cell division.
Paclitaxel was first isolated in 1971 from the
Pacific yew and
approved for medical use in 1993. It is on the World Health
Organization's List of Essential Medicines, the most effective and
safe medicines needed in a health system. The wholesale cost in the
developing world is about 7.06 to 13.48 USD per 100 mg vial.
This amount in the United Kingdom costs the
NHS about 66.85 pounds.
It is now manufactured by cell culture.
1 Medical use
1.1 Similar compounds
2 Side effects
3 Mechanism of action
5.1 Plant screening program
5.2 Early clinical trials, supply and the transfer to BMS
6 Society and culture
8 Additional images
11 External links
Paclitaxel is approved in the UK for ovarian, breast and lung,
bladder, prostate, melanoma, esophageal, and other types of solid
tumor cancers as well as Kaposi's sarcoma. It is recommended in
NICE guidance of June 2001 that it should be used for nonsmall cell
lung cancer in patients unsuitable for curative treatment, and in
first-line and second-line treatment of ovarian cancer. In September
NICE recommended paclitaxel should be available for the
treatment of advanced breast cancer after the failure of anthracyclic
chemotherapy, but that its first-line use should be limited to
clinical trials. In September 2006,
NICE recommended paclitaxel should
not be used in the adjuvant treatment of early node-positive breast
cancer. In 2005, its use in the United States for the treatment of
breast, pancreatic, and non-small cell lung cancers was approved by
Albumin-bound paclitaxel (trade name Abraxane, also called
nab-paclitaxel) is an alternative formulation where paclitaxel is
bound to albumin nano-particles. Much of the clinical toxicity of
paclitaxel is associated with the solvent
Cremophor EL in which it is
dissolved for delivery.
Abraxis BioScience developed Abraxane, in
which paclitaxel is bonded to albumin as an alternative delivery agent
to the often toxic solvent delivery method. This was approved by the
Food and Drug Administration
Food and Drug Administration in January 2005 for the treatment of
breast cancer after failure of combination chemotherapy for metastatic
disease or relapse within six months of adjuvant chemotherapy.
Synthetic approaches to paclitaxel production led to the development
Docetaxel has a similar set of clinical uses to
paclitaxel and is marketed under the name of Taxotere.
Recently the presence of taxanes including paclitaxel,
10-deacetylbaccatin III, baccatin III, paclitaxel C, and
7-epipaclitaxel in the shells and leaves of hazel plants has been
reported. The finding of these compounds in shells, which are
considered discarded material and are mass-produced by many food
industries, is of interest for the future availability of paclitaxel.
Paclitaxel is used as an antiproliferative agent for the prevention of
restenosis (recurrent narrowing) of coronary and peripheral stents;
locally delivered to the wall of the artery, a paclitaxel coating
limits the growth of neointima (scar tissue) within stents.
Paclitaxel drug eluting coated stents for coronary artery placement
are sold under the trade name Taxus by
Boston Scientific in the United
Paclitaxel drug eluting coated stents for femoropopliteal
artery placement are sold under the trade name Zilver PTX by Cook
Common side effects include nausea and vomiting, loss of appetite,
change in taste, thinned or brittle hair, pain in the joints of the
arms or legs lasting two to three days, changes in the color of the
nails, and tingling in the hands or toes. More
serious side effects such as unusual bruising or bleeding,
pain/redness/swelling at the injection site, hand-foot syndrome,
change in normal bowel habits for more than two days, fever, chills,
cough, sore throat, difficulty swallowing, dizziness, shortness of
breath, severe exhaustion, skin rash, facial flushing, female
infertility by ovarian damage, and chest pain can also occur.[citation
Neuropathy may also occur.
Dexamethasone is given prior to beginning paclitaxel treatment to
mitigate some of the side effects.
A number of these side effects are associated with the excipient used,
Cremophor EL, a polyoxyethylated castor oil, and allergies to
cyclosporine, teniposide, and other drugs containing polyoxyethylated
castor oil may indicate increased risk of adverse reactions to
Mechanism of action
Complex of α, β tubulin subunits and paclitaxel.
Paclitaxel is shown
as yellow stick.
Paclitaxel is one of several cytoskeletal drugs that target tubulin.
Paclitaxel-treated cells have defects in mitotic spindle assembly,
chromosome segregation, and cell division. Unlike other
tubulin-targeting drugs such as colchicine that inhibit microtubule
assembly, paclitaxel stabilizes the microtubule polymer and protects
it from disassembly. Chromosomes are thus unable to achieve a
metaphase spindle configuration. This blocks the progression of
mitosis and prolonged activation of the mitotic checkpoint triggers
apoptosis or reversion to the G-phase of the cell cycle without cell
The ability of paclitaxel to inhibit spindle function is generally
attributed to its suppression of microtubule dynamics, but recent
studies have demonstrated that suppression of dynamics occurs at
concentrations lower than those needed to block mitosis. At the higher
therapeutic concentrations, paclitaxel appears to suppress microtubule
detachment from centrosomes, a process normally activated during
Paclitaxel binds to beta-tubulin subunits of
Pacific yew bark contains paclitaxel and related
The bark is peeled and processed to provide paclitaxel.
From 1967 to 1993, almost all paclitaxel produced was derived from
bark from the Pacific yew, the harvesting of which kills the tree in
the process. The processes used were descendants of the original
isolation method of Monroe Wall and Mansukh Wani; by 1987, the NCI had
contracted Hauser Chemical Research of Boulder, Colorado, to handle
bark on the scale needed for Phase II and III trials.
While both the size of the wild population of Taxus brevifola and the
magnitude of the eventual demand for taxol were uncertain, it was
clear for many years[vague] that an alternative, sustainable source of
supply of the natural product would be needed. Initial attempts to
broaden its sourcing used needles from the tree, or material from
other related Taxus species, including cultivated ones,[citation
needed] but these attempts were challenged by the relatively low and
often highly variable yields obtained. Early in the 1990s, coincident
with increased sensitivity to the ecology of the forests of the
Pacific Northwest, paclitaxel was successfully extracted on a
clinically useful scale from these sources.
Concurrently, synthetic chemists in the US and France had been
interested in taxol, beginning in the late 1970s. As
noted, by 1992 extensive efforts were underway to accomplish the total
synthesis of paclitaxel, efforts motivated by the desire to generate
new chemical understanding rather than to achieve practical commercial
production. In contrast, the French group of
Pierre Potier at the
Centre national de la recherche scientifique (CNRS) addressed the
matter of overall process yield, showing that it was feasible to
isolate relatively large quantities of the compound
10-deacetylbaccatin from the European yew, Taxus baccata, which grew
CNRS campus and whose needles were available in large
quantity. By virtue of its structure,
10-deacetylbaccatin was seen as a viable starting material for a short
semisynthesis to produce taxol. By 1988 Poitier and collaborators had
published a semisynthetic route from needles of T. baccata to
The view of the NCI, however, was even this route was not
practical. The group of
Robert A. Holton had also
pursued a practical semisynthetic production route; by late 1989,
Holton's group had developed a semisynthetic route to paclitaxel with
twice the yield of the Potier process. Florida State
University, where Holton worked, signed a deal with Bristol-Myers
Squibb to license their semisynthesis and future patents.[citation
needed] In 1992, Holton patented an improved process with an 80%
yield, and BMS took the process in-house and started to manufacture
paclitaxel in Ireland from
10-deacetylbaccatin isolated from the
needles of the European yew. In early 1993, BMS
announced that it would cease reliance on
Pacific yew bark by the end
of 1995, effectively terminating ecological controversy over its
use. This announcement also made good their
commitment to develop an alternative supply route, made to the NCI in
their CRADA application of 1989.
As of 2013, paclitaxel production for BMS is sourced using a
semisynthetic method from
Taxus baccata (European yew). Another
company which worked with BMS until 2012, Phyton Biotech, Inc.,
uses plant cell fermentation (PCF) technology. By cultivating a
specific Taxus cell line in fermentation tanks, they no longer need
ongoing sourcing of material from actual yew tree plantations.
Paclitaxel is then captured directly from the suspension broth by a
resin allowing concentration to highly enriched powder containing
about 40% paclitaxel. The compound is then purified by one
chromatographic step followed by crystallization. Compared to the
semisynthesis® , PCF eliminates the need for many hazardous chemicals
and saves a considerable amount of energy.
In 1993, taxol was discovered as a natural product in a newly
described endophytic fungus living in the yew tree. It has since
been reported in a number of other endophytic fungi, including
Nodulisporium sylviforme, Alternaria taxi, Cladosporium
cladosporioides MD2, Metarhizium anisopliae, Aspergillus candidus MD3,
Mucor rouxianus, Chaetomella raphigera, Phyllosticta tabernaemontanae,
Phomopsis, Pestalotiopsis pauciseta, Phyllosticta citricarpa,
Podocarpus sp., Fusarium solani, Pestalotiopsis terminaliae,
Pestalotiopsis breviseta, Botryodiplodia theobromae, Gliocladium sp.,
Alternaria alternata var. monosporus, Cladosporium cladosporioides,
Nigrospora sp., Pestalotiopsis versicolor, and Taxomyces andreanae.
However, there has been contradictory evidence for its production by
endophytes, with other studies finding independent production is
The core synthetic route is via a terpenoid pathway, parts of which
having been successfully transplanted into production strains of
E.coli and yeast.
Paclitaxel total synthesis
Paclitaxel, with rings labeled and accepted numbering scheme shown.
By 1992, at least thirty academic research teams globally were working
to achieve a total synthesis of this natural product, with the
synthesis proceeding from simple natural products and other readily
available starting materials. This total synthesis effort was
motivated primarily by the desire to generate new chemical
understanding, rather than with an expectation of the practical
commercial production of paclitaxel. The first laboratories to
complete the total synthesis from much less complex starting materials
were the research groups of Robert A. Holton, who had the first
article to be accepted for publication, and of
K. C. Nicolaou who had
the first article to appear in print (by a week, on 7 February 1994).
Though the Holton submission preceded the Nicolaou by a month (21
December 1993 versus 24 January 1994), the near coincidence of the
publications arising from each of these massive, multiyear
efforts—11–18 authors appearing on each of the February 1994
publications—has led the ending of the race to be termed a "tie"
or a "photo finish", though each group has argued that their
synthetic strategy and tactics were superior.
As of 2006, five additional research groups had reported successful
total syntheses of paclitaxel: Wender et al. in 1997, and Kuwajima et
al. and Mukaiyama et al. in 1998 with further linear syntheses, and
Danishefsky et al. in 1996 and Takahashi et al. in 2006 with further
convergent syntheses.[needs update] As of that date, all strategies
had aimed to prepare a 10-Deacetylbaccatin-type core containing the
ABCD ring system, followed generally by last stage addition of the
"tail" to the 13-hydroxyl group.
While the "political climate surrounding taxol and
Taxus brevifolia in
the early 1990s… helped bolster [a] link between total synthesis and
the [taxol] supply problem", and though total synthesis activities
were a requisite to explore the structure-activity relationships of
taxol via generation of analogs for testing, the total synthesis
efforts were never seen "as a serious commercial route" to provide
significant quantities of the natural product for medical testing or
The discovery of paclitaxel began in 1962 as a result of a U.S.
Cancer Institute-funded screening program. A number of
years later it was isolated from the bark of the Pacific yew, Taxus
brevifolia, hence its name "taxol".
The discovery was made by
Monroe E. Wall
Monroe E. Wall and
Mansukh C. Wani
Mansukh C. Wani at the
Research Triangle Institute, Research Triangle Park, North Carolina,
in 1971. These scientists isolated the natural product from the
bark of the
Pacific yew tree, Taxus brevifolia, determined its
structure and named it "taxol", and arranged for its first biological
testing. The compound was then developed commercially
Bristol-Myers Squibb (BMS), who had the generic name assigned as
Plant screening program
In 1955, the National
Cancer Institute (NCI) in the United States set
Chemotherapy National Service Center (CCNSC) to act as a
public screening center for anticancer activity in compounds submitted
by external institutions and companies. Although the majority of
compounds screened were of synthetic origin, one chemist, Jonathan
Hartwell, who was employed there from 1958 onwards, had experience
with natural product derived compounds, and began a plant screening
operation. After some years of informal arrangements, in July
1960, the NCI commissioned
USDA botanists to collect samples from
about 1,000 plant species per year. On 21 August 1962, one of
those botanists, Arthur S. Barclay, collected bark from a single
Pacific yew tree, Taxus brevifolia, in a forest north of the town of
Packwood, Washington as part of a four-month trip to collect material
from over 200 different species. The material was then processed by a
number of specialist CCNSC subcontractors, and one of the Taxus
samples was found to be cytotoxic in a cellular assay on 22 May
Accordingly, in late 1964 or early 1965, the fractionation and
isolation laboratory run by
Monroe E. Wall
Monroe E. Wall in Research Triangle Park,
North Carolina, began work on fresh Taxus samples, isolating the
active ingredient in September 1966 and announcing their findings at
an April 1967
American Chemical Society
American Chemical Society meeting in Miami Beach.
They named the pure compound taxol in June 1967. Wall and his
colleague Wani published their results, including the chemical
structure, in 1971.
The NCI continued to commission work to collect more Taxus bark and to
isolate increasing quantities of taxol. By 1969, 28 kg of crude
extract had been isolated from almost 1,200 kg of bark, although
this ultimately yielded only 10 g of pure material, but for
several years, no use was made of the compound by the NCI. In 1975, it
was shown to be active in another in vitro system; two years later, a
new department head reviewed the data and finally recommended taxol be
moved on to the next stage in the discovery process. This required
increasing quantities of purified taxol, up to 600 g, and in 1977 a
further request for 7,000 lbs of bark was made.
In 1978, two NCI researchers published a report showing taxol was
mildly effective in leukaemic mice. In November 1978, taxol was
shown to be effective in xenograft studies. Meanwhile, taxol began
to be well known in the cell biology, as well as the cancer community,
with a publication in early 1979 by Susan B. Horwitz, a molecular
pharmacologist at Albert Einstein College of Medicine, showing taxol
had a previously unknown mechanism of action involving the
stabilization of microtubules. Together with formulation problems,
this increased interest from researchers meant that, by 1980, the NCI
envisaged needing to collect 20,000 lbs of bark. Animal
toxicology studies were complete by June 1982, and in November NCI
applied for the IND necessary to begin clinical trials in humans.
Early clinical trials, supply and the transfer to BMS
Phase I clinical trials began in April 1984, and the decision to start
Phase II trials was made a year later. These larger trials needed
more bark and collection of a further 12,000 pounds was commissioned,
which enabled some phase II trials to begin by the end of 1986. But by
then it was recognized that the demand for taxol might be substantial
and that more than 60,000 pounds of bark might be needed as a minimum.
This unprecedentedly large amount brought ecological concerns about
the impact on yew populations into focus for the first time, as local
politicians and foresters expressed unease at the program.
The first public report from a phase II trial in May 1988 showed an
effect in melanoma patients and a remarkable response rate of 30% in
patients with refractory ovarian cancer. At this point, Gordon
Cragg of the NCI's Natural Product Branch calculated the synthesis of
enough taxol to treat all the ovarian cancer and melanoma cases in the
US would require the destruction of 360,000 trees annually. For the
first time, serious consideration was given to the problem of
supply. Because of the practical and, in particular, the financial
scale of the program needed, the NCI decided to seek association with
a pharmaceutical company, and in August 1989, it published a
Cooperative Research and Development Agreement (CRADA) offering its
current stock and supply from current bark stocks, and proprietary
access to the data so far collected, to a company willing to commit to
providing the funds to collect further raw material, isolate taxol,
and fund a large proportion of clinical trials. In the words of
Goodman and Welsh, authors of a substantial scholarly book on taxol,
"The NCI was thinking, not of collaboration, ... but of a hand-over of
taxol (and its problems)".
Although the offer was widely advertised, only four companies
responded to the CRADA, including the American firm Bristol-Myers
Squibb (BMS), which was selected as the partner in December 1989. The
choice of BMS later became controversial and was the subject of
Congressional hearings in 1991 and 1992. While it seems clear the NCI
had little choice but to seek a commercial partner, there was also
controversy about the terms of the deal, eventually leading to a
report by the
General Accounting Office
General Accounting Office in 2003, which concluded the
NIH had failed to ensure value for money. In related CRADAs with
USDA and Department of the Interior,
Bristol-Myers Squibb was
given exclusive first refusal on all Federal supplies of Taxus
brevifolia. This exclusive contract lead to some criticism for giving
BMS a "cancer monopoly". Eighteen months after the CRADA, BMS
filed a new drug application (NDA), which was given FDA approval at
the very end of 1992.  Although there was no patent on the
compound, the provisions of the Waxman-Hatch Act gave Bristol-Myers
Squibb five years exclusive marketing rights.
In 1990, BMS applied to trademark the name taxol as Taxol(R). This was
controversially approved in 1992. At the same time, paclitaxel
replaced taxol as the generic (INN) name of the compound. Critics,
including the journal Nature, argued the name taxol had been used for
more than two decades and in more than 600 scientific articles and
suggested the trademark should not have been awarded and the BMS
should renounce its rights to it. BMS argued changing the name
would cause confusion among oncologists and possibly endanger the
health of patients. BMS has continued to defend its rights to the name
in the courts. BMS has also been criticized for misrepresentation
by Goodman and Walsh, who quote from a company report saying "It was
not until 1971 that ... testing ... enabled the isolation of
paclitaxel, initially described as 'compound 17". This quote is,
strictly speaking, accurate: the objection seems to be that this
misleadingly neglects to explain that it was the scientist doing the
isolation who named the compound taxol and it was not referred to in
any other way for more than twenty years.
Annual sales peaked in 2000, reaching US$1.6 billion; paclitaxel is
now available in generic form. In October 2007 it was approved by Drug
controller General of India for the treatment of breast cancer and
launched by collaboration with Biocon.
Society and culture
The nomenclature for paclitaxel is structured on a tetracyclic
17-carbon (heptadecane) skeleton. There are a total of 11
stereocenters. The active stereoisomer is (−)-paclitaxel (shown
(benzoylamino)-2-hydroxy-3- phenylpropanoyl]oxy -1,9-
[188.8.131.52~3,10~.0~4,7~] heptadec-13-en-2-yl rel-benzoate
As of 2006[update], the cost to the
NHS per patient in early breast
cancer, assuming four cycles of treatment, was about £4000 (approx.
A recent study suggested that caffeine may inhibit paclitaxel-induced
apoptosis in colorectal cancer cells.
Aside from its direct clinical use, paclitaxel is used extensively in
biological and biomedical research as a microtubule stabilizer. In
general, in vitro assays involving microtubules, such as motility
assays, rely on paclitaxel to maintain microtubule integrity in the
absence of the various nucleating factors and other stabilizing
elements found in the cell. For example, it is used for in vitro tests
of drugs that aim to alter the behavior of microtubule motor proteins,
or for studies of mutant motor proteins. Moreover,
Paclitaxel has been
used in vitro to inhibit insulin fibrillation; in a molar ratio of
10:1 (insulin:paclitaxel), it hindered insulin fibrillation near 70%.
Iso-thermal titration calorimetry (ITC) findings indicated a
spontaneous tendency of paclitaxel to interact with insulin through
hydrogen bonds and van der Waal’s forces. Also, the inhibitory
role of paclitaxel is attributed to its impact on the colloidal
stability of protein solution, as it was observed that paclitaxel
inhibited lysozyme fibrillation by inducing the formation of
"off-pathway" oligomeric intermediates and increasing the colloidal
stability subsequently .
Paclitaxel is sometimes used for in vivo
studies as well; it can be fed to test organisms, such as fruit flies,
or injected into individual cells, to inhibit microtubule disassembly
or to increase the number of microtubules in the cell. Paclitaxel
induces remyelination in a demyelinating mouse in vivo and
inhibits hPAD2 in vitro though its methyl ester side chain.
Angiotech Pharmaceuticals Inc. began phase II clinical trials in
1999 as a multiple sclerosis treatment but in 2002, reported that
the results showed no statistical significance.
In 2016 in vitro multi-drug resistant mouse tumor cells were treated
with paclitaxel encased in exosomes. Doses 98% less than common dosing
had the same effect. Also, dye-marked exosomes were able to mark tumor
cells, potentially aiding in diagnosis.
Space-filling model of paclitaxel
Rotating paclitaxel molecule model
Crystal structure of paclitaxel
Total charge surface of taxol. Minimum energy conformation.
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^ a b c Nina Hall, 2003, Creating complexity: The beauty and logic of
synthesis, Chem. Commun., 661 – 664, doi:10.1039/b212248k
^ See N. Hall, ibid. See also the American Chemical Society
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^ ME, WALL; MC, Wani (February 15, 1995). "amptothecin and taxol:
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^ Goodman & Walsh 2001, p. 22.
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^ Goodman & Walsh 2001, p. 81.
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taxol, an antineoplastic agent from Taxus brevifolia, acts as a
mitotic spindle poison".
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^ Goodman & Walsh 2001, p. 95.
^ a b Goodman & Walsh 2001, p. 97
^ Goodman & Walsh 2001, p. 115.
^ a b c d Goodman & Walsh 2001, p. 120
^ Rowinsky, EK; et al. (1988). "Phase II study of taxol in advanced
epithelial malignancies". Proceedings of the Association of Clinical
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^ Nader, Ralph; Love, James. "Looting the medicine chest: how
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^ "Names for hi-jacking". Nature. 373 (6513): 370. 1995.
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^ Goodman & Walsh 2001, p. 170.
^ Bristol-Myers Squibb, The development of TAXOL (paclitaxel), March
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U.S. National Library of Medicine: Drug Information
Intracellular chemotherapeutic agents / antineoplastic agents
Block microtubule assembly
Vinca alkaloids (Vinblastine#
Block microtubule disassembly
Dihydrofolate reductase inhibitor
Dihydrofolate reductase inhibitor (Aminopterin
Thymidylate synthase inhibitor (Raltitrexed
Adenosine deaminase inhibitor
Adenosine deaminase inhibitor (Pentostatin)
Halogenated/ribonucleotide reductase inhibitors (Cladribine
Thymidylate synthase inhibitor (Fluorouracil#
DNA polymerase inhibitor (Cytarabine#)
Ribonucleotide reductase inhibitor (Gemcitabine#)
Hypomethylating agent (Azacitidine
Ribonucleotide reductase inhibitor (Hydroxycarbamide#)
Crosslinking of DNA
Nitrogen mustards: Mechlorethamine
Aminolevulinic acid / Methyl aminolevulinate
Porphyrin derivatives (Porfimer sodium
CDK inhibitors (Abemaciclib
PARP inhibitor (Niraparib
Retinoid X receptor (Bexarotene)
Sex steroid (Testolactone)
Asparagine depleters (Asparaginase#/Pegaspargase)
‡Withdrawn from market
§Never to phase III
TRP channel modulators
Sanshool (ginger, Sichuan and melegueta peppers)
Allyl isothiocyanate (mustard, radish, horseradish, wasabi)
CR gas (dibenzoxazepine; DBO)
CS gas (2-chlorobenzal malononitrile)
Farnesyl thiosalicylic acid
Ligustilide (celery, Angelica acutiloba)
Linalool (Sichuan pepper, thyme)
Methyl salicylate (wintergreen)
Oleocanthal (olive oil)
Paclitaxel (Pacific yew)
Polygodial (Dorrigo pepper)
Shogaols (ginger, Sichuan and melegueta peppers)
Thiopropanal S-oxide (onion)
Umbellulone (Umbellularia californica)
Adhyperforin (St John's wort)
Hyperforin (St John's wort)
Cooling Agent 10
Rutamarin (Ruta graveolens)
Steviol glycosides (e.g., stevioside) (Stevia rebaudiana)
Sweet tastants (e.g., glucose, fructose, sucrose; indirectly)
Rutamarin (Ruta graveolens)
Triptolide (Tripterygium wilfordii)
Sanshool (ginger, Sichuan and melegueta peppers)
Bisandrographolide (Andrographis paniculata)
Camphor (camphor laurel, rosemary, camphorweed, African blue basil,
Capsaicin (chili pepper)
Carvacrol (oregano, thyme, pepperwort, wild bergamot, others)
Dihydrocapsaicin (chili pepper)
Eugenol (basil, clove)
Evodiamine (Euodia ruticarpa)
Homocapsaicin (chili pepper)
Homodihydrocapsaicin (chili pepper)
Low pH (acidic conditions)
Nonivamide (PAVA) (PAVA spray)
Nordihydrocapsaicin (chili pepper)
Paclitaxel (Pacific yew)
Phorbol esters (e.g., 4α-PDD)
Piperine (black pepper, long pepper)
Polygodial (Dorrigo pepper)
Rutamarin (Ruta graveolens)
Resiniferatoxin (RTX) (Euphorbia resinifera/pooissonii)
Shogaols (ginger, Sichuan and melegueta peppers)
Thymol (thyme, oregano)
Tinyatoxin (Euphorbia resinifera/pooissonii)
Cannabigerolic acid (cannabis)
See also: Receptor/signaling modulators • Ion channel modulators
Xenobiotic-sensing receptor modulators
DHEA-S (prasterone sulfate)
Hypericum perforatum (St John's wort)
Nuclear receptor modulators
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