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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).

Lignans
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

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 6.2.1.12), 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 1.1.1.195), 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 1.10.3.2). 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.

Lignans
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 1.23.1.2), is first reduced to (+)-lariciresinol, and then to (-)-secoisolariciresinol. (-)-Secoisolariciresinol, in the reaction catalyzed by NAD(P)-dependent secoisolariciresinol dehydrogenase (EC 1.1.1.331) 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.

Lignans
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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References

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

Tsao R. Chemistry and biochemistry of dietary polyphenols. Nutrients 2010;2:1231-46. doi:10.3390/nu2121231

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

Wink M. Biochemistry of plant secondary metabolism – 2nd Edition. Annual plant reviews (v. 40), Wiley J. & Sons, Inc., Publication, 2010

Green tea: definition, processing, properties, polyphenols

What is green tea?

Green tea is an infusion of processed leaves of tea plant, Camellia sinensis, a member of the Theaceae family.
It is the most consumed beverages in Asia, particularly in China and Japan.
Western populations consume black tea more frequently than green tea. However, in recent years, thanks to its health benefits, it has been gaining their attention.
Currently, it accounts for 20% of the tea consumed worldwide.

“You can never get a cup of tea large enough or a book long enough to suit me.”C.S. Lewis

Processing and properties of green tea

Green Tea
Fig. 1 – Camellia sinensis

As all other types of tea, it is produced from fresh leaves of Camellia sinensis.
The peculiar properties of the beverage depend on the type of processing that the leaves undergo. In fact, they are processed in such a way as to minimize both enzymatic and chemical oxidation processes of the substances contained in them, in particular catechins.
Therefore, among the different types of tea, it undergoes the lowest degree of oxidation during processing.
At the end of the processing, tea leaves retain their green color, thanks to the little chemical modifications/oxidations they have undergone. The infusion shows off a yellow-gold color.
Finally, the processing of tea leaves ensures that green tea flavor is more delicate and lighter than black tea.

The three main steps in the processing of green tea

After harvesting, tea leaves are exposed to the sun for 2-3 hours and withered/dried; then, the real processing starts.
It consists of three main steps: heat treatment, rolling and drying.

Heat treatment

Heat treatment, short and gentle, is the crucial step for the quality and properties of the beverage.
It occurs with steam (the traditional Japanese method) or by dry cooking in hot pans (a large wok, the traditional Chinese method). Heat treatment has the purpose of:

  • inactivate the enzymes present in the tissues of the leaves, thus stopping enzymatic oxidation processes, particularly of polyphenols;
  • eliminate the grassy smell in order to stand out tea flavor;
  • evaporate part of the water present in the fresh leaf (water constitutes about 75% of the weight of the leaf), making it softer, so as to make the next step easier.

Rolling

The rolling step follows the heat treatment of the leaves; this step has the purpose of:

  • facilitate the next stage of drying;
  • destroy the tissues of the leaves in order to favor, later, the release of aromas, thus improving the quality of the product.

Drying

The drying is the last step, which also leads to the production of new compounds and improves the appearance of the product.

Green tea polyphenols

Gree Tea
Fig. 2 – EGCG

All types of tea are rich in polyphenols, compounds that are also present in fruits, vegetables, extra virgin olive oil, and red wine.
Fresh tea leaves are rich in water-soluble polyphenols, especially catechins (or flavanols) and glycosylated catechins (both belonging to the class of flavonoids), molecules which are believed to be the responsibles of the benefits of green tea.
The major catechins in green tea are epigallocatechin-3-gallate (EGCG), epigallocatechin, epicatechin-3-gallate, epicatechin, epicatechin, but also catechin, gallocatechin, catechin gallate, and gallocatechin gallate are present, even if in lower amount. These polyphenols account for 30%-42% of the dry leaf weight (but only 3%–10% of the solid content of black tea).
Green tea caffeine accounts for 1,5-4,5% of the dry leaf weight.

How to maximize the absorption of green tea catechins

In vitro studies have shown the high antioxidant power of catechins, greater than that of vitamin C and vitamin E. In vitro, EGCG is generally considered the most biologically active catechin.
In vivo studies and several epidemiologic studies have shown the possible preventive effects of green tea catechins, especially EGCG, in preventing the development of:

  • cardiovascular disease, such as hypertension and stroke;
  • some cancers, such as lung cancer (but not among smokers) and oral and digestive tract cancers.

For these reasons, it is essential to maximize the intestinal absorption of catechins.
Catechins are stable in acidic environment, but not in non-acidic environment, as in the small intestine; also for this reason, after digestion, less than 20% of the total remains.
Studies with models of the digestive tract of rat and man, that simulate digestion in stomach and small intestine, have shown that the addition of citrus juice or vitamin C to green tea significantly increases the absorption of catechins.
Among tested citrus juices, lemon juice is the best, followed by orange, lime and grapefruit juices. Citrus juices seem to have a stabilizing effect on catechins that goes beyond what would be predicted solely based on their ascorbic acid content.

References

Clifford M.N., van der Hooft J.J.J., and Crozier A. Human studies on the absorption, distribution, metabolism, and excretion of tea polyphenols. Am J Clin Nutr 2013;98:1619S-1630S [Abstract]

Dwyer J.T. and Peterson J. Tea and flavonoids: where we are, where to go next. Am J Clin Nutr 2013;98:1611S-1618S [Abstract]

Green R.J., Murphy A.S., Schulz B., Watkins B.A. and Ferruzzi M.G. Common tea formulations modulate in vitro digestive recovery of green tea catechins. Mol Nutr Food Res 2007;51(9):1152-1162 [Abstract]

Huang W-Y., Lin Y-R., Ho R-F., Liu H-Y., and Lin Y-S. Effects of water solutions on extracting green tea leaves. ScientificWorldJournal 2013;Article ID 368350 [Abstract]

Sharma V.K., Bhattacharya A., Kumar A. and Sharma H.K. Health benefits of tea consumption. Trop J Pharm Res 2007;6(3):785-792 [Abstract]

Green tea benefits for health

Benefits of green tea: science and myths

Green Tea Benefits
Fig. 1 – Green Tea Benefits

Tea drinking, particularly green tea, has always been associated, at least in East Asia cultures (mainly in China and Japan) with health benefits. Only recently, the scientific community has begun to study the health benefits of tea consumption, recognizing its preventive value in many diseases.

Green tea benefits in preventing cancer

Several epidemiological and laboratory studies have shown encouraging results with respect to possible preventive role of tea, particularly green tea and its catechins, a subgroup of flavonoids (the most abundant polyphenols in human diet) against the development of some cancers like:

  • oral and digestive tract cancers;
  • lung cancer among those who have never smoked, not among smokers.

Tea polyphenols, the most active of which is epigallocatechin-3-gallate (EGCG), seem to act not only as antioxidants, but also as molecules that, directly, may influence gene expression and diverse metabolic pathways.

Green tea benefits in cardiovascular disease

Cardiovascular disease is the main cause of deaths worldwide, particularly in low- and middle-income countries, with an estimate of about 17 million deaths in 2008 that will increase up to 23.3 million by 2030.
Daily tea consumption, especially green tea, seems to be associated with a reduced risk of developing cardiovascular disease, such as hypertension and stroke.
Among the proposed mechanisms, the improved bioactivity of the endothelium-derived vasodilator nitric oxide (NO), due to the action of tea polyphenols that enhance nitric oxide synthesis, and/or decrease superoxide-mediated nitric oxide breakdown seem to be important.

Drinking a daily cup of tea will surely starve the apothecary.” Chinese proverb

Green tea benefits and antioxidant properties

Tea polyphenols may act, in vitro, as free radical scavengers.
Since radical damage plays a pivotal role in the development of many diseases such as atherosclerosis, rheumatoid arthritis, cancer, or in ischemia-reoxygenation injury, tea polyphenols, particularly green tea catechins, may have a preventive role.

Green tea benefits in weight loss and weight maintenance

Green tea, but also oolong tea, that is, catechins and caffeine rich teas, has a potential thermogenic effect. This has made them a potential tool for:

  • weight loss, by increasing energy expenditure and fat oxidation;
  • weight maintenance, ensuring a high energy expenditure during the maintenance of weight loss.

Indeed, it has been shown that green tea and green tea extracts are not an aid in weight loss and weight maintenance, since:

  • they are not able to induce a significant weight loss in overweight and obese adults;
  • they are not helpful in the maintenance of weight loss.

Green tea benefits in preventing dental decay

Animal and in vitro studies have shown that tea, and in particular its polyphenols, seems to possess:

  • antibacterial properties against pathogenic action of cariogenic bacteria, as Streptococcus mutans, particularly green tea EGCG;
  • inhibitory action on salivary and bacterial amylase (it seems that black tea thearubigins and theaflavins are more effective than green tea catechins);
  • it is able to inhibit acid production in the oral cavity.

All these properties make green tea and black tea, beverages with potential anticariogenic activity.

References