Before We Get Started
What Are Flavonoids?
Flavonoids are chemicals that are based on the simple skeleton structure of “Flavan”. The structure is provided below. The term “Flavonoid” is based on the Latin term Flavus which means “Yellow”. Many of the colors exhibited by flavonoids are white, yellow, red, blue, purple and even black. Flavonoids can be divided into six (6) different groups: Flavans, Flavanols, Flavanones, Flavones, Flavonols, and anthocyanidins. For the sake of simplicity, when we refer to these chemicals in the broadest of categories, we will use the term “Flavonoid(s)”. Flavonoids belong to a larger family of chemicals called polyphenols. Polyphenol is a common name for compounds that contain a phenyl or benzene ring with an alcohol or -OH, oxygen hydrogen, group. But wait, you may remember that CBD has two hydroxy, -OH groups, attached to its phenyl ring. Why is CBD called a cannabinoid and not a Flavonoid? Let’s take a look at the structures below to compare CBD with a polyphenol, Flavan, and a representative flavonoid.
Flavonoids are defined by a special structural feature starting with the benzopyran ring, numbered 1 through 8 in the Flavan structure above, with a phenyl group attached at the number two or three positions of the benzopyran ring. For all the pertinent flavonoids in cannabis, we will find the phenyl ring attached at the two position of the benzopyran ring. The phenyl ring is numbered 1’, one-prime, through 5’, five-prime. While CBD has a similar arrangement of hydroxy groups on its phenyl ring, like that in Catechin, CBD does not contain the benzopyran ring, and therefore; it is not a flavonoid. There are over 8000 polyphenols known and nearly 4,000 of these are flavonoids. There are about 25 major flavonoids found in cannabis. These cannabis flavonoids can only be found in the buds, leaves, and stalk of the plant, but not in the seeds or roots. For us, the importance of flavonoids is their potential health benefits. The benzopyran ring is the most predominate structural feature of a flavonoid. A pyran ring is a cyclic six-member ring containing 5 carbons on one oxygen. Benzene is a cyclic six-member ring with 6 carbons. Benzopyran is represented as a ringed structure such that there are a total of 9 carbons and one oxygen in what is termed a “Fused Ring”. In flavonoids, this 10-atom, fused structure of benzene and pyran, is called a “Benzopyran”. The numbering starts at the oxygen and goes clockwise around the structure, as shown in the example of Flavan. In Part I, we will be discussing those flavonoids that are in the categories of Flavan, Flavanols, Flavanones, and Flavanonols. Notice all these flavonoid terms start with the prefix “Flava-.” The term flava- is used when the benzopyran ring does not contain a carbon-carbon double bond between the positions 2 and 3. When the double bond does exist, then the prefix will be “Flavo-. Notice the letter “O” instead of “A”. But we will get in more detail about that in Part II. The naming suffixes of -nol, -none, and -nonol give use a clue as to what is substituted on the pyran portion of the benzopyran ring, besides the phenyl group at the 2 position. The term “-nol” refers to a hydroxy group. The term “-none” refers to a carbon-oxygen double bond group. And the term “-nonol” is a combination of both hydroxy and carbon-oxygen bond groups being present on the pyran portion of the benzopyran ring. You will find in many flavonoids hydroxy groups attached to the fused benzene ring of the benzopyran group and the phenyl group attached at carbon number 2. The attached hydroxy groups are considered to be functional substitutions that do not impact the base name of the flavonoid. See the basic structures for the different categories of Flavonoids below.
Let’s look at this list of “Flava” flavonoids and see what their potential health benefits are.
These two flavans are representations of polymerized flavans found in cannabis.Polymerized flavonoids are generally conjugated from flavans and flavanols. There are no simple flavans in sufficient abundance to be found in cannabis. Polymerized flavans can be the source of bitter and acidic flavors in foods. Colorations from the polymerized flavonoids can range from red to black. They are most commonly found in the tannins of unripe fruits and vegetables, as well as red wines, tea, and cocoa, besides cannabis.
Theaflavin has been shown to be an effective adjunct to a low-saturated-fat diet to reduce Low Density Lipoprotein, LDL, in hypercholesterolemic adults and it is well tolerated. Theaflavins have strong antioxidative property and is able to neutralize free-radicals and increase the activity of detoxifying enzymes found in the liver. Theaflavins have also been used for headaches, reducing blood pressure, preventing heart disease, and disrupting the formation of β-Amyloid Plaque. Maybe you have heard of this last term. β-Amyloid Plaque is the buildup of Amyloid β-Protein on brain structures which is produced by an enzyme in the family of β-secretases. BACE1 is an acronym for beta-site amyloid precursor protein cleaving enzyme 1, which is the specific β-secretase causing plaque buildup on brain neurons. This protein plaque buildup has been determined to be the cause of Alzheimer’s Disease. Amyloid β-protein (Aβ) is a small unstructured protein with unknown physiological function. In Alzheimer’s Disease, Amyloid β-Protein, produced by BACE1, self-assembles into metastable, toxic oligomers that injure neurons and synapses, disrupting neuronal communication, and causing gradual neurodegeneration in susceptible brain areas, predominantly those responsible for memory and cognitive function. Theaflavin has been shown to have activity in disrupting the pathways of this Amyloid β-protein plaque formation. It has also been shown to dissolute, breakup, this plaque build-up and help return function back to the neurons and synapses. The biggest issue in treating Alzheimer’s with Theaflavin, at this time, is the amount of Theaflavin that can cross the Blood-Brain-Barrier and reach the affected neurons. While recent studies have shown benefits of Theaflavin for Alzheimer’s Disease, this research is still in its early phase.
Studies suggest that thearubigins also benefit the body and mind in many ways, including lessening the effects of coughs and colds, and providing anti-inflammatory effects; thereby, reducing the impact of illnesses such as Irritable Bowel Syndrome, and cancers of prostate and melanoma. Thearubigins, and theaflavins, have also been shown to reduce low-density lipoprotein by about 10%. Researchers have determined that these beneficial effects can be obtained from the consumption of these complex flavonoids found in green and black teas, and cannabis. Polymerized flavonoids, because of their structural complexity, do not absorb quickly into the blood stream and have difficulties in crossing the Blood Brain Barrier in significant amounts. However, continued consumption of these flavonoids can lower the risk of many of the diseases mentioned above through a number of different mechanisms.
Catechin is a flavanol since there is no carbon-carbon double bond in the pyran ring between the carbons numbered 2 and 3, yet contains a hydroxy group, -OH group, at the 3 position. Therefore, the prefix Flava- ends in the suffix -nol; flavanol. Catechin has many potential benefits including assistance in weight loss and cancer prevention, such as breast and prostate cancer, similar to the Theaflavins. Catechin has been shown to aid in both brain and heart health. It assists in the regulation of diabetes and may also offer protection from the sun’s UV rays as a topical. Catechins have also been shown to reduce platelet-clumping, similar to the activity provided by the approved product Plavix. Because of this effect, Catechin can improve endothelial function. Endothelial cells form a single layer that lines all blood vessels. A side benefit of Plavix is the reduction of existing plaque buildup in blood vessels. Catechin’s ability of preventing platelet-clumping helps reduce the risk of embolism formation and Catechin may help reduce the amount of existing plaque buildup in a similar manner to that of Plavix.
As anticipated, flavanones do not contain a carbon-carbon double bond between the 2 and 3 positions of the pyran ring portion of benzopyran, hence the prefix of the name being Flava-. These structures contain a carbon-oxygen double bond at the 4 position and no hydroxy group at the 3 position; therefore, the name’s suffix is -none, hence the term flavanone.
Naringenin is endowed with broad biological effects on human health, which includes a decrease in lipid peroxidation biomarkers and protein carbonylation. It promotes carbohydrate metabolism, increases antioxidative defenses, scavenges reactive oxygen species, modulates immune system activity, and also exerts anti-atherogenic and anti-inflammatory effects. It has been reported to have significant ability to modulate signaling pathways related to fatty acid metabolism, which favors fatty acid oxidation, impairs lipid accumulation in the liver and thereby preventing formation of fatty liver disease. It also impairs plasma lipids and lipoprotein accumulation in the liver. In addition, Naringenin potentiates intracellular signaling responses to the presence of low insulin levels by sensitizing hepatocytes to increase insulin production. Naringenin is also able to traverse the blood–brain barrier and exert diverse neuronal effects through its ability to interact with protein kinase C signaling pathways.
Flavanonols contains the carbon-oxygen double bond at the 4 position, a hydroxy group at the 3 position, but does not contain a carbon-carbon double bond between positions 2 and 3. Therefore, the prefix is Flava-, rather than Flavo-, and ends with the combination of -none and -nol, as -nonol; hence the name, flavanonol.
Taxifolin is also known as Dihydroquercetin. Dihydro-is another way of saying that there is not a carbon-carbon double bond present in the benzopyran ring. This means that Quercetin and Taxifolin have the same chemical structure except for the presence or absence, respectively, of the carbon-carbon double bond between positions 2 and 3 of the benzopyran ring. Taxifolin is commonly found in cannabis, onions, milk thistle, French maritime pine bark and Douglas fir bark. Taxifolin shows promising pharmacological activities in the management of inflammation, tumors, microbial infections, cardiovascular and liver disorders, provides improvement of cognitive functions and shows immunoprotective activity. Its anti-cancer benefit is the most prominent activity amongst the list of benefits given as demonstrated in different in vitro and in vivo models. In vitro refers to studies performed in cell cultures and not directly on human or animal models. In vivo refers to examining the efficacy of substances by direct administration to humans or animal models, like the people who volunteered to be guinea pigs for the Covid-19 vaccine trials.
Aromadendrin is also known as Dihydrokaempferol. We will see Kaempferol in Part II. Aromadendrin is known for its antioxidative properties and is currently being evaluated as a treatment for skin cancer, specifically melanoma. Aromadendrin is another flavonoid that stimulates glucose uptake and upregulates insulin production that may be useful in type 2 diabetes. Upregulating insulin is characterized as breaking down the insulin resistance barrier. Therefore, this flavonoid should have benefits targeted to weight loss and glucose control in diabetic patients. Of course, being a flavonoid from cannabis, Aromadendrin has significant antioxidative and antimicrobial properties and most likely shares a number of other potential health benefits of the flavonoids, terpenes and cannabinoids found in cannabis.
And in a Special Category
Naringenin Chalcone, the precursor to Naringenin, is not officially a flavonoid because it does not possess the benzopyran ring, but because it is an essential intermediate in the biosynthesis of flavonoids and the direct precursor to naringenin, mentioned above, chalcones are listed in the grouping of Flavonoids. Naringenin Chalcone has demonstrated significant anti-allergic activity using an in vitro histamine-release assay. This chalcone exerts the strongest inhibition of histamine release compared to other flavonoids isolated and also shows protective effects in the in vivo mouse model. Naringenin Chalcone also shows the strongest in vivo histamine release profile, anti-allergic effects, compared to other polyphenols. The biosynthetic pathway of Naringenin Chalcone and Naringenin is shown below.
Biosynthesis of this Naringenin chalcone and the subsequent formation of Naringenin starts with a common amino acid, Phenylalanine. Naringenin can be converted to other flavonoids and produce some unique structures, which we will see in Part II.
What Are Flavonoids?
The term “Flavonoid” is based on the Latin term Flavus which means “Yellow”.
Many of the colors exhibited by flavonoids are white, yellow, red, blue, purple and even black.
Can Flavonoids Be Divided Into Groups?
How Many Flavonoids Are Found In Cannabis?
These cannabis flavonoids can only be found in the buds, leaves, and stalk of the plant, but not in the seeds or roots.