Gingerol (
gingerol) is a
phenol
Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it req ...
ic
phytochemical
Phytochemicals are chemical compounds produced by plants, generally to help them resist fungi, bacteria and plant virus infections, and also consumption by insects and other animals. The name comes . Some phytochemicals have been used as poisons ...
compound found in fresh
ginger
Ginger (''Zingiber officinale'') is a flowering plant whose rhizome, ginger root or ginger, is widely used as a spice
A spice is a seed, fruit, root, bark, or other plant substance primarily used for flavoring or coloring food. Spices ...
that activates spice receptors on the tongue. It is normally found as a pungent yellow oil in the ginger rhizome, but can also form a low-melting crystalline solid. This chemical compound is found in all members of the
Zingiberaceae
Zingiberaceae () or the ginger family is a family of flowering plants made up of about 50 genera with a total of about 1600 known species of aromatic perennial herbs with creeping horizontal or tuberous rhizomes distributed throughout tropical Af ...
family and is high in concentrations in the
grains of paradise
''Aframomum melegueta'' is a species in the ginger family, Zingiberaceae, and closely related to cardamom. Its seeds are used as a spice (ground or whole); it imparts a pungent, black-pepper-like flavor with hints of citrus. It is commonly ...
as well as an African Ginger species.
Cooking ginger transforms gingerol via a
reverse aldol reaction into
zingerone
Zingerone, also called vanillylacetone, is a major flavor component of ginger, providing the sweet flavor of cooked ginger. Zingerone is a crystalline solid that is sparingly soluble in water and soluble in ether.
Zingerone is similar in chemica ...
, which is less pungent and has a spicy-sweet aroma. When ginger is dried or mildly heated, gingerol undergoes a
dehydration reaction
In chemistry, a dehydration reaction is a chemical reaction that involves the loss of water from the reacting molecule or ion. Dehydration reactions are common processes, the reverse of a hydration reaction.
Dehydration reactions in organic che ...
forming
shogaol
Shogaols are pungent constituents of ginger similar in chemical structure to gingerol. The most common of the group is shogaol. Like zingerone, it is produced when ginger is dried or cooked. Moreover, shogaol (and gingerol) are converted to o ...
s, which are about twice as pungent as gingerol.
NSF International
NSF (an initialism for National Sanitation Foundation) is a product testing, inspection, certification organization with headquarters in Ann Arbor, Michigan. NSF also offers consulting and training services worldwide.
History
NSF Internatio ...
''Determination of Gingerols and Shogaols in Zingiber officinale rhizome and powdered extract by High-Performance Liquid Chromatography'' This explains why dried ginger is more pungent than fresh ginger.
Ginger also contains
gingerol,
0gingerol, and
2gingerol, collectively deemed gingerols.
Physiological potential
In a pre-clinical meta-analysis of gingerol compounds anticancer, anti-inflammatory, anti-fungal,
antioxidant, neuroprotective
and gastroprotective properties were reported, which include studies ''
in-vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' and ''
in-vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and pl ...
''.
A few ''in-vivo'' studies have proposed that gingerols facilitate healthy glucose regulation for diabetics.
Many studies have been around the effects of gingerols on a wide range of cancers including
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
,
prostate
The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...
,
breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and secret ...
,
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
,
ovarian
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
,
lung
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
,
pancreatic
The pancreas is an Organ (anatomy), organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...
and
colorectal
The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being ...
.
There has not been much clinical testing to observe gingerols physiological impacts in humans.
While many of the chemical mechanisms associated with the effects of gingerols on cells have been thoroughly studied, few have been in a clinical setting. This is due to the high variability in natural
phytochemical
Phytochemicals are chemical compounds produced by plants, generally to help them resist fungi, bacteria and plant virus infections, and also consumption by insects and other animals. The name comes . Some phytochemicals have been used as poisons ...
s and the lack of efficacy in research.
Most herbal medicine, which include gingerols, are under the restrictions of the
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
in the United States and experimental methods have not held up to scrutiny which has decreased the value in phytochemical research.
Herbal medicine is untested for quality assurance, potency and effectiveness in clinical settings due to a lack of funding in eastern medical research.
Most research on
Gingerol has been on either mouse subjects (''in-vivo'') or on cultured human tissue (''in-vitro'') and may be used in the future to discuss possible applications for multi-target disease control.
An investigation scrutinizing gingerol's anti-fungal capabilities remarked that an African species of ginger tested higher in both gingerol and shogaol compounds than the more commonly cultivated Indonesian relative.
When tested for the anti-fungal properties the African ginger combated against 13 human
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
s and was three times more effective than the commercial Indonesian counterpart.
It is thought that gingerol compounds work in tandem with the other phytochemicals present including
shogaol
Shogaols are pungent constituents of ginger similar in chemical structure to gingerol. The most common of the group is shogaol. Like zingerone, it is produced when ginger is dried or cooked. Moreover, shogaol (and gingerol) are converted to o ...
s,
paradol
Paradol is the active flavor constituent of the seeds of Guinea pepper (''Aframomum melegueta'' or grains of paradise). It is also found in ginger. Paradol has been found to have antioxidant and antitumor promoting effects in a mouse model.
It ...
s and
zingerone
Zingerone, also called vanillylacetone, is a major flavor component of ginger, providing the sweet flavor of cooked ginger. Zingerone is a crystalline solid that is sparingly soluble in water and soluble in ether.
Zingerone is similar in chemica ...
.
In a meta analysis looking at many different phytochemical effects on prostate cancer, two specific studies using mice observed
gingerol compounds induced apoptosis in cancer cells by interfering with the
mitochondrial membrane
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...
.
There were also observed mechanisms associated with the disruption of G1 phase proteins to stop the reproduction of cancer cells which is also an associated benefit of other relevant anticancer studies.
The main mechanism by which gingerol phytochemicals act on cancer cells seems to be protein disruption. The
anti-carcinogenic An anticarcinogen (also known as a carcinopreventive agent) is a substance that counteracts the effects of a carcinogen or inhibits the development of cancer. Anticarcinogens are different from anticarcinoma agents (also known as anticancer or ant ...
activity of
gingerol and
paradol was analysed in a study observing the cellular mechanisms associated with mouse skin cancer which targeted the activator proteins associated with tumor initiation. Gingerol compounds inhibited the transformation of normal cells into cancer cells by blocking AP-1 proteins and when cancer did develop paradol encouraged
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
due to its
cytotoxic
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa'').
Cell physiology
Treating cells ...
activity.
Gingerol exhibits cell cycle arrest capabilities, apoptotic action and enzyme-coupled cell signaling receptor degradation in cancer cells. Gingerol has been observed to stop proliferation through inhibiting the translation of Cyclin proteins necessary for replication during G1 and G2 phase of cell division. To promote apoptosis in cancer cells
Cytochrome C
The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...
is ejected from the mitochondria which ceases ATP production leaving a dysfunctional mitochondria. The Cytochrome C assembles an
apoptosome
The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal (intrinsic) or external (extrinsic) cell death st ...
which activates the
Caspase-9
Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such ...
and initiates an executioner Caspase cascade, effectively breaking down DNA into
histones
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
and promoting apoptosis.
Gingerol also inhibits the anti-apoptotic Bcl-2 proteins on the surface of mitochondria, which in turn increases the capabilities for the pro-apoptotic Bcl-2 proteins to initiate cell death. Cancer cells exhibit high amounts of growth hormone activator proteins that are expressed through enzyme-coupled signaling pathways. By halting the phosphorylation of PI-3-Kinase the Akt protein cannot bind with its PH domain, effectively deactivating the downstream signal. Successively keeping Bad proteins bound to anti-apoptotic proteins which keeps them from promoting cell growth, consequently, a double negative cellular signaling pathway to promote apoptosis.
Cultured human breast cancer cells were subjected to various concentrations of
gingerol to determine the impacts on live cells. These concentration dependent results concluded that there was no impact at 5 μM but a reduction of 16% occurred at 10 μM.
gingerol targeted three specific proteins in breast cancer cells that promote
metastasis
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
and while adhesion remained relatively unchanged,
gingerol inhibited the cancer cells from invading and increasing in size.
This study suggests the mechanism by which cancer cell growth was impacted was due to a reduction in specific mRNA that transcribes for extracellular degrading enzymes called
matrix metalloproteinases
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...
(MMP's).
An examination using human cells ''in-vitro'' displayed gingerols capabilities in combating oxidative stress. The results concluded that gingerol had anti-inflammatory effects though shogaol showed the most promising effects combating free radicals.
There was an inverted dose- concentration response and as dosage concentration increased the amount of
free radicals
In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron.
With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spont ...
in cells decreased.
Cisplatin
Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, br ...
is a chemotherapy drug that if used in high dosages causes renal failure which is considered a limiting factor for this life saving drug. By using
gingerol it prevented the occurrence of renal failure in rats.
gingerol improved
glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...
production in dose-dependent results which suggested that the higher a dosage the more of an effect
gingerol had.
Gingerol compounds are thought to help in
diabetic
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased app ...
patients because of increases in glutathione, a cellular toxin regulatory factor.
Anti-
hyperglycaemic effects were studied in diabetic and severely obese mice. Gingerol compounds increased glucose uptake in cells without the need of a synthetic insulin activator, while also decreasing fasting glucose and increasing glucose tolerance.
In a different study the exact metabolic mechanisms associated with the physiological benefits of gingerol phytochemicals concluded that there was increased
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
activity (CAT) and glutathione production while decreasing
lipoprotein
A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
cholesterol and improving glucose tolerance in mice.
Cardio-arrhythmia is a common side effect of diabetic patients and the anti-inflammatory effects of gingerol suppressed the risks by lowering blood glucose levels ''in-vivo''.
The anti-oxidant properties of
gingerol has been considered as a defense against
Alzheimer’s
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
. A study observed the molecular mechanisms responsible for the protection against
DNA fragmentation
DNA fragmentation is the separation or breaking of DNA strands into pieces. It can be done intentionally by laboratory personnel or by cells, or can occur spontaneously. Spontaneous or accidental DNA fragmentation is fragmentation that gradually a ...
and mitochondrial membrane potential deterioration of cells which suggests a neuroprotective support of gingerol.
This study indicates that ginger up-regulates glutathione production in cells, including nerve cells, through anti-oxidative properties which decreases the risk of Alzheimer's in human
neuroblastoma
Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the ...
cells and mouse
hippocampal
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...
cells.
While many studies suggest the low risk of using ginger phytochemicals to combat oxidation damage to cells, there are a few studies that suggest potential
genotoxic Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with Mutagen, mutagenicity, all mutagens are genotoxic, but some geno ...
effects. In one study too high of a dose to human hepatoma cells resulted in DNA fragmentation,
chromosomal
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
damage and
organelle
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...
membrane instability which could result in apoptotic behavior.
There are some pro-oxidant behaviors to gingerol compounds when the concentration reaches high levels although also considered, in normal conditions these phytochemicals observed have anti-inflammatory and anti-oxidant qualities.
In another study
Gingerol notably inhibited the metabolic rate of rats when given an
intraperitoneal injection
Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity). It is more often applied to animals than to humans. In general, it is preferred when large amounts of blood replacement fluids are needed ...
which induced a
hypothermic
Hypothermia is defined as a body core temperature below in humans. Symptoms depend on the temperature. In mild hypothermia, there is shivering and mental confusion. In moderate hypothermia, shivering stops and confusion increases. In severe h ...
reaction though, when consumed orally in excess there were no changes in body temperature.
Biosynthesis
Both
ginger
Ginger (''Zingiber officinale'') is a flowering plant whose rhizome, ginger root or ginger, is widely used as a spice
A spice is a seed, fruit, root, bark, or other plant substance primarily used for flavoring or coloring food. Spices ...
(''Zingiber officinale'') and
turmeric
Turmeric () is a flowering plant, ''Curcuma longa'' (), of the ginger family, Zingiberaceae, the rhizomes of which are used in cooking. The plant is a perennial, rhizomatous, herbaceous plant native to the Indian subcontinent and Southeast Asi ...
(''Curcuma longa'') had been suspected to utilize
phenylpropanoid
The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acids phenylalanine and tyrosine. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of ...
pathway and produce putative type III polyketide synthase products based on the research of 6-gingerol biosynthesis by Denniff and Whiting in 1976 and by Schröder's research in 1997.
6-Gingerol is the major gingerol in ginger rhizomes and it possesses some interesting pharmacological activities like analgesic effect. While the biosynthesis of 6-gingerol is not fully elucidated, plausible pathways are presented here.
In the proposed biosynthetic pathway, Scheme 1, L-Phe (1) is used as the starting material. It is converted into
Cinnamic acid
Cinnamic acid is an organic compound with the formula C6H5-CH=CH- COOH. It is a white crystalline compound that is slightly soluble in water, and freely soluble in many organic solvents. Classified as an unsaturated carboxylic acid, it occurs n ...
(2) via phenylalanine ammonia lyase (PAL). Then it is turned into
p-Coumaric acid (3) with use of cinnamate 4-hydroxylase (C4H). 4-coumarate:CoA ligase (4CL) is then used to get
p-Coumaroyl-CoA (5). P-Coumaroyl shikimate transferase (CST) is the enzyme that is responsible for the bonding of
shikimic acid
Shikimic acid, more commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a cyclohexanecarboxylic acid. It is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower ''shi ...
and p-Coumaroyl-CoA. The complexed (5) is then selectively oxidized at C3 by p-coumaroyl 5-O-shikimate 3'-hydroxylase (CS3'H) to alcohol. With another action of CST, shikimate is broken off from this intermediate, thereby yielding
Caffeoyl-CoA (7). In order to get desired substitution pattern on the aromatic ring, caffeoyl-CoA O-methyltransferase (CCOMT) converts the hydroxyl group at C3 into methoxy as seen in
Feruloyl-CoA (8). Up until this step, according to Ramirez-Ahumada et al., the enzyme activities are very active.
It is speculated that some polyketide synthases (PKS) and reductases are involved in final synthesis of 6-Gingerol (10).
Because it is unclear whether the methoxy group addition is performed before or after the condensation step of the polyketide synthase, alternative pathway is shown in Scheme 2, where methoxy group is introduced after PKS activity. In this alternative pathway, the enzymes involved are likely to be cytochrome p450 hydroxylases, and
S-adenosyl-L-methionine
''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
-dependent O-methyltransferases (OMT).
There are three possibilities for the reduction step by Reductase: directly after PKS activity, after PKS and Hydroxylase activity, or in the end after PKS, Hydroxylase, and OMT activity.
References
External links
Stilbenoid, diarylheptanoid and gingerol biosynthesis pathway at genome.jp
{{Transient receptor potential channel modulators
O-methylated natural phenols
Ginger
Pungent flavors
Ketones
Secondary alcohols