Tag Archives: lignans

Lignans: definition, chemical structure, biosynthesis, metabolism, foods

Lignans: contents in brief

What are lignans?

Lignans are a subgroup of non-flavonoid polyphenols.
They are widely distributed in the plant kingdom, being present in more than 55 plant families, where they act as antioxidants and defense molecules against pathogenic fungi and bacteria.
In humans, epidemiological and physiological studies have shown that they can exert positive effects in the prevention of lifestyle-related diseases, such as type II diabetes and cancer. For example, an increased dietary intake of these polyphenols correlates with a reduction in the occurrence of certain types of estrogen-related tumors, such as breast cancer in postmenopausal women.
In addition, some lignans have also aroused pharmacological interest. Examples are:

  • podophyllotoxin, obtained from plants of the genus Podophyllum (Berberidaceae family); it is a mitotic toxin whose derivatives have been used as chemotherapeutic agents;
  • arctigenin and tracheologin, obtained from tropical climbing plants; they have antiviral properties and have been tested in the search for a drug to treat AIDS .

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Chemical structure of lignans

Their basic chemical structure consists of two phenylpropane units linked by a C-C bond between the central atoms of the respective side chains (position 8 or β), also called β-β’ bond. 3-3′, 8-O-4′, or 8-3′ bonds are observed less frequently; in these cases the dimers are called neolignans. Hence, their chemical structure is referred to as (C6-C3)2, and they are included in the phenylpropanoid group, as well as their precursors: the hydroxycinnamic acids (see below).

Fig. 1 – Phenylpropane unit

Based on their carbon skeleton, cyclization pattern, and the way in which oxygen is incorporated in the molecule skeleton, they can be divided into 8 subgroups: furans, furofurans, dibenzylbutanes, dibenzylbutyrolactones, dibenzocyclooctadienes, dibenzylbutyrolactols, aryltetralins and arylnaphthalenes. Furthermore, there is considerable variability regarding the oxidation level of both the propyl side chains and the aromatic rings.
They are not present in the free form in nature, but linked to other molecules, mainly as glycosylated derivatives.
Among the most common lignans, secoisolariciresinol (the most abundant one), lariciresinol, pinoresinol, matairesinol and 7-hydroxymatairesinol are found.

Note: They occur not only as dimers but also as more complex oligomers, such as dilignans and sesquilignans.

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Biosynthesis of lignans

Fig. 2 – Lignan Biosynthesis

In this section, we will examine the synthesis of some of the most common lignans.
The pathway starts from 3 of the 4 most common dietary hydroxycinnamic acids: p-coumaric acid, sinapic acid, and ferulic acid (caffeic acid is not a precursor of this subgroup of polyphenols). Therefore, they arise from the shikimic acid pathway, via phenylalanine.
The first three reactions reduce the carboxylic group of the hydroxycinnamates to alcohol group, with formation of the corresponding alcohols, called monolignols, that is, p-coumaric alcohol, sinapyl alcohol and coniferyl alcohol. These molecules also enter the pathway of lignin biosynthesis.

  • The first step, which leads to the activation of the hydroxycinnamic acids, is catalysed by hydroxycinnamate:CoA ligases, commonly called p-coumarate:CoA ligases (EC, with formation of the corresponding hydroxycinnamate-CoAs, namely, feruloil-CoA, p- coumaroyl-CoA and sinapil-CoA.
  • In the second step, a NADPH-dependent cinnamoyl-CoA: oxidoreductase, also called cinnamoyl-CoA reductase (EC1.2.1.44) catalyzes the formation of the corresponding aldehydes, and the release of coenzyme A.
  • In the last step, a NADPH-dependent cinnamyl alcohol dehydrogenase, also called monolignol dehydrogenase (EC, catalyzes the reduction of the aldehyde group to an alcohol group, with the formation of the aforementioned monolignols.

The next step, the dimerization of monolignols, involves the intervention of stereoselective mechanisms, or, more precisely, enantioselective mechanisms. In fact, most of the plant lignans exists as (+)- or (-)-enantiomers, whose relative amounts can vary from species to species, but also in different organs on the same plant, depending on the type of reactions involved.
The dimerization can occur through enzymatic reactions involving laccases (EC These enzymes catalyze the formation of radicals that, dimerizing, form a racemic mixture. However, this does not explain how the enantiomeric mixtures found in plants are formed. The most accepted mechanism to explain the stereospecific synthesis involves the action of the laccase and of a protein able to direct the synthesis toward one or the other of the two enantiomeric forms: the dirigent protein. The reaction scheme might be: the enzyme catalyzes the synthesis of phenylpropanoid radicals that are orientated in such a way to obtain the desired stereospecific coupling by the dirigent protein.

Fig. 3 – (-)-Matairesinol

For example, pinoresinol synthase, consisting of laccase and dirigent protein, catalyzes the stereospecific synthesis of (+)-pinoresinol from two units of coniferyl alcohol. (+)-Pinoresinol, in two consecutive stereospecific reactions catalyzed by NADPH-dependent pinoresinol/lariciresinol reductase (EC, is first reduced to (+)-lariciresinol, and then to (-)-secoisolariciresinol. (-)-Secoisolariciresinol, in the reaction catalyzed by NAD(P)-dependent secoisolariciresinol dehydrogenase (EC is oxidized to (-)-matairesinol.

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Metabolism of lignans by human gut microbiota

Their importance to human health is due largely to their metabolism by colonic microbiota, which carries out deglycosylations, para-dehydroxylations, and meta-demethylations without enantiomeric inversion. Indeed, this metabolization leads to the formation molecules with a modest estrogen-like activity (phytoestrogens), a situation similar to that observed with some isoflavones, such as those of soybean, some coumarins, and some stilbenes. These active metabolites are the so-called “mammalian lignans or enterolignans”, such as the aglycones of enterodiol and enterolactone, formed from secoisolariciresinol and matairesinol, respectively.
Studies conducted on animals fed diets rich in lignans have shown their presence as intact molecules, in low concentrations, in serum, suggesting that they may be absorbed as such from the intestine. These molecules exhibit estrogen-independent actions, both in vivo and in vitro, such as inhibition of angiogenesis, reduction of diabetes, and suppression of tumor growth.
Note: The term “phytoestrogen” refers to molecules with estrogenic or antiandrogenic activity, at least in vitro.

Once absorbed, they enter the enterohepatic circulation, and, in the liver, may undergo phase II reactions and be sulfated or glucuronidated, and finally excreted in the urine.

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Food rich in lignans

The richest dietary source is flaxseed (linseed), that contains mainly secoisolariciresinol, but also lariciresinol, pinoresinol and matairesinol in good quantity (for a total amount of more than 3.7 mg/100 g dry weight). They are also found in sesame seeds.

Fig. 4 – (-)-Secoisolariciresinol

Another important source is whole grains.
They are also present in other foods, but in concentrations from one hundred to one thousand times lower than those of flaxseed. Examples are:

  • beverages, generally more abundant in red wine, followed in descending order by black tea, soy milk and coffee;
  • fruits, such as apricots, pears, peaches, strawberries;
  • among vegetables, Brassicaceae, garlic, asparagus and carrots;
  • lentils and beans.

Their presence in grains and, to a lesser extent in red wine and fruit, makes them, at least in individuals who follow a Mediterranean-style eating pattern, the main source of phytoestrogens.

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Andersen Ø.M., Markham K.R. Flavonoids: chemistry, biochemistry, and applications. CRC Press Taylor & Francis Group, 2006

de la Rosa L.A., Alvarez-Parrilla E., Gonzàlez-Aguilar G.A. Fruit and vegetable phytochemicals: chemistry, nutritional value, and stability. 1th Edition. Wiley J. & Sons, Inc., Publication, 2010

Heldt H-W. Plant biochemistry – 3th Edition. Elsevier Academic Press, 2005

Manach C., Scalbert A., Morand C., Rémésy C., and Jime´nez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004;79(5):727-47 [Abstract]

Satake H, Koyama T., Bahabadi S.E., Matsumoto E., Ono E. and Murata J. Essences in metabolic engineering of lignan biosynthesis. Metabolites 2015;5:270-90. doi:10.3390/metabo5020270

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van Duynhoven J., Vaughan E.E., Jacobs D.M., Kemperman R.A., van Velzen E.J.J, Gross G., Roger L.C., Possemiers S., Smilde A.K., Doré J., Westerhuis J.A.,and Van de Wiele T. Metabolic fate of polyphenols in the human superorganism. PNAS 2011;108(suppl. 1):4531-8. doi:10.1073/pnas.1000098107

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Polyphenols in olive oil: variability and chemical composition

Polyphenols in olive oil: contents in brief

Polyphenols in olive oil: influences of environment and extraction process

Polyphenols in Olive Oil
Fig. 1 – Olives

Olive oil, which is obtained from the pressing of the olives, the fruits of olive tree (Olea europaea), is the main source of fat in the Mediterranean diet, and a good source of polyphenols.
Polyphenols, natural antioxidants, are present in olive pulp and, following pressing, they pass into the oil.
Note: olives are also known as drupes or stone fruits.
The concentration of polyphenols in olive oil is the result of a complex interaction between various factors, both environmental and linked to the extraction process of the oil itself, such as:

  • the place of cultivation;
  • the cultivars (variety);
  • the level of ripeness of the olives at the time of harvesting.
    Their level usually decreases with over-ripening of the olives, although there are exceptions to this rule. For example, in  warmer climates, olives produce oils richer in polyphenols, in spite of their faster maturation.
  • the climate;
  • the extraction process. In this regard, it is to underscore that the content of polyphenol in refined olive oil is not significant.

Any variation of the concentration of different polyphenols influence the taste, nutritional properties and stability of olive oil. For example, hydroxytyrosol and oleuropein (see below) give extra virgin olive oil a pungent and bitter taste.

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Key polyphenols in olive oil

Among polyphenols in olive oil, there are  molecules with simple structure, such as phenolic acids and alcohols, and molecules with complex structure, such as flavonoids, secoiridoids, and lignans.

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Flavonoids include glycosides of flavonols (rutin, also known as quercetin-3-rutinoside), flavones (luteolin-7-glucoside), and anthocyanins (glycosides of delphinidin).

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Phenolic acids and phenolic alcohols

Among phenolic acids, the first polyphenols with simple structure observed in olive oil, they are found:

  • hydroxybenzoic acids, such as, gallic, protocatechuic, and 4-hydroxybenzoic acids (all with C6-C1 structure).
  • hydroxycinnamic acids, such as  caffeic, vanillin, syringic, p-coumaric, and o-coumaric acids (all with C6-C3 structure).

Among phenolic alcohols, the most abundant are hydroxytyrosol (also known as  3,4-dihydroxyphenyl-ethanol), and tyrosol [also known as 2-(4-hydroxyphenyl)-ethanol].

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Hydroxytyrosol can be present as:

  • simple phenol;
  • phenol esterified with elenolic acid, forming oleuropein and its aglycone;
  • part of the molecule verbascoside.
Polyphenols in olive oil
Fig. 2 – Hydroxytyrosol

It can also be present in different glycosidic forms, depending on the –OH group to which the glucoside, i.e. elenolic acid plus glucose, is bound.
It is one of the main polyphenols in olive oil, extra virgin olive oil, and olive vegetable water.
In nature, its concentration, such as that of tyrosol, increases during fruit ripening, in parallel with the hydrolysis of compounds with higher molecular weight, while the total content of phenolic molecules and alpha-tocopherol decreases. Therefore, it can be considered as an indicator of the degree of ripeness of the olives.
In fresh extra virgin olive oil, hydroxytyrosol is mostly present in esterified form, while in time, due to hydrolysis reactions, the non-esterified form becomes the predominant one.
Finally, the concentration of hydroxytyrosol is correlated with the stability of olive oil.

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They are the polyphenols in olive oil with the more complex structure, and are produced from the secondary metabolism of terpenes.
They are glycosylated compounds and are characterized by the presence of elenolic acid in their structure (both in its aglyconic or glucosidic form). Elenolic acid is the molecule common to glycosidic secoiridoids of Oleaceae.
Unlike tocopherols, flavonoids, phenolic acids, and phenolic alcohols, that are found in many fruits and vegetables belonging to different botanical families, secoiridoids are present only in plants of the Oleaceae family.
Oleuropein, demethyloleuropein, ligstroside, and nuzenide are the main secoiridoids.
In particular, oleuropein and demethyloleuropein (as verbascoside) are abundant in the pulp, but they are also found in other parts of the fruit. Nuzenide is only present in the seeds.

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Oleuropein, the ester of hydroxytyrosol and elenolic acid, is the most important secoiridoid, and the main olive oil polyphenol.

Polyphenols in Olive Oil
Fig. 3 – Oleuropein

It is present in very high quantities in olive leaves, as also in all the constituent parts of the olive, including peel, pulp and kernel.
Oleuropein accumulates in olives during the growth phase, up to 14% of the net weight; when the fruit turns greener, its quantity reduces. Finally, when the olives turns dark brown, color due to the presence of anthocyanins, the reduction in its concentration becomes more evident.
It was also shown that its content is greater in green cultivars than in black ones.
During the reduction of oleuropein levels (and of the levels of other secoiridoids), an increase of compounds such as flavonoids, verbascosides, and simple phenols can be observed.
The reduction of its content is also accompanied by an increase in its secondary glycosylated products, that reach the highest values in black olives.

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Polyphenols in olive oil
Fig. 4 – Lignans

Lignans, in particular (+)-1- acetoxypinoresinol and (+)-pinoresinol, are another group of polyphenols in olive oil.
(+)-pinoresinol is a common molecule in the lignin fraction of many plants, such as sesame (Sesamun indicum) and the seeds of the species Forsythia, belonging to the family Oleaceae. It has been also found in the olive kernel.
(+)-1- acetoxypinoresinol and (+)-1-hydroxypinoresinol, and their glycosides, have been found in the bark of the olive tree.
Lignans are not present in the pericarp of the olives, nor in leaves and sprigs that may accidentally be pressed with the olives.
Therefore, how  they can pass into the olive oil becoming one of the main phenolic fractions is not yet known.
(+)-1- acetoxypinoresinol and (+)-pinoresinol are absent in seed oils, are virtually absent from refined virgin olive oil, while they may reach a concentration of 100 mg/kg in extra-virgin olive oil.
As seen for simple phenols and secoiridoids, there is considerable variation in their concentration among olive oils of various origin, variability probably related to differences between olive varieties,  production areas, climate, and oil production techniques.

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Cicerale S., Lucas L. and Keast R. Biological activities of phenolic compounds present in virgin olive oil. Int. J. Mol. Sci. 2010;11: 458-479. doi:10.3390/ijms11020458

de la Rosa L.A., Alvarez-Parrilla E., Gonzàlez-Aguilar G.A. Fruit and vegetable phytochemicals: chemistry, nutritional value, and stability. 1th Edition. Wiley J. & Sons, Inc., Publication, 2010

Manach C., Scalbert A., Morand C., Rémésy C., and Jime´nez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004;79(5):727-47 [Abstract]

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