Grape phytochemicals A bouquet of old and new

Medical Hypotheses (2006) 67, 833–838

http://intl.elsevierhealth.com/journals/mehy

Grape phytochemicals: A bouquet of old and new nutraceuticals for human health Marcello Iriti *, Franco Faoro ` di Milano and CNR, Dipartimento Agroalimentare, Istituto di Patologia Vegetale Universita Istituto di Virologia Vegetale, Via Celoria, 2, 20133 Milano, Italy Received 10 March 2006; accepted 13 March 2006

Summary Health benefits associated with Mediterranean diets are due to the significantly large intake of functional plant foods and beverages, i.e., fruits, vegetables, cereals, legumes, nuts, wine, beer, and olive oil, containing a great array of bioactive phytochemicals or nutraceutical compounds. Therefore, the low risk of chronic diseases, such as coronary hearth disease and certain cancers, observed in some population groups, results from a diversified eating style, either in term of foods and food components. The paradigm of the relationship between the chemical diversity of a particular food and the array of its biological activities may be symbolized by grape. Despite the extensive knowledge about phenylpropanoids, principally polyphenols (stilbenes and anthocyanins) and condensed tannins (proanthocyanidins), in grape and wine, little it is known about the other compounds, such as tetrahydro-b-carbolines. Recently, it has been attached importance to the dietary indoleamines, melatonin, and serotonin, in different plant foods, including grape, thus further supporting the hypothesis that health benefits, associated with Mediterranean dietary style, are due to plant food chemical diversity. c 2006 Elsevier Ltd. All rights reserved.

Gignit et humores melius vinum meliores (The best men come from the best wine) Regimen Sanitatis. Flos Medicinae Scholae Salerni, XI° cent.

Introduction In their natural environment, plants have to cope with an array of stress conditions to improve their fitness. For plants, stress factors include drought, * Corresponding author. Tel.: +39 0250316786; fax: +39 0250316781.

E-mail addresses: marcello.iriti@unimi.it (M. Iriti), franco. faoro@unimi.it (F. Faoro).

salinity, nutritional deficiency, intense insolation, adverse climatic conditions, pollutants, pathogens, insects, and phytophagy. Therefore, plant species survival depends on their genomic plasticity, i.e., the ability of diversifying their own defence responses against the above mentioned biotic and abiotic stresses. Besides, because of plant sessile status, synthesis of phytochemicals represents a major strategy for counteracting unfavourable conditions, in terms of natural selection, biological evolution, and biodiversity. The most plant bioactive substances are mainly secondary metabolites, not directly involved in development, growth, and reproduction, but entailed in plant ecological networks.

0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2006.03.049

834 Plant natural products can be roughly ascribed to three main classes of compounds, phenylpropanoids, isoprenoids, and alkaloids, widely distributed in plant foods and medicinal herbs [1–3].

Thereby, a great array of molecules, derived from plant secondary metabolism, are of extreme interest in human nutrition and pharmacology, in addition to perfumery and cosmetic industries.

Plant-derived foodstuffs and beverages include mainly fruits, vegetables, herbs, spices, chocolate, tea, beer, and wine, also known as functional foods and beverages. These are in no way pharmaceuticals, but diet components able to ameliorate human fitness, in other words the so-called nutraceuticals [4].

A valuable source of nutraceuticals is represented by grape (Vitis vinifera) and wine, as recently emphasized by a growing body of knowledge [5]. At the beginning of the nineties, the ‘French paradox’ symbolized paradigmatically the health benefits due to regular and moderate consumption of wine. This term refers to the low incidence of atherosclerotic cardiovascular disease in the French population, in spite of a diet rich in total and saturated fat, because of moderate daily red wine drinking [6]. Promptly, it was hypothesized, and then extensively demonstrated, that the observed epidemiological relationship between wine intake and health benefits was attributable to the red wine polyphenolic fraction [7].

The main grape and wine nutritional characteristics were mostly associated to their content in phenylpropanoids, despite the great variety of chemicals in these commodities. With this regard, the recent discovery of melatonin, an indolic compound, in different grapevine cultivars [8], adds a new element to the plethora of health benefits associated to wine consumption.

Grape chemistry Pharmaconutrients of grape, mostly detected in berry skins and seeds, arise from different metabolic pathways (Fig. 1). Phenylpropanoid biosynthetic route leads to simple phenols or phenolic acids, flavonoids, stilbenes, and proanthocyanidins [9]. Simple phenols occurring in Vitis include hydroxybenzoic and hydroxycinnamic acids [10].

Flavonoids are separated into flavonols, flavanols, and anthocyanins. Flavanols provide catechin and epicatechin, the monomeric units of proanthocyanidins, whereas anthocyanins are pigments responsible for wine color [11]. Resveratrol is the major stilbene, in addition to the uncommon piceids, pterostilbenes, and viniferins, respectively,

Iriti and Faoro resveratrol glucosides, dimethylated resveratrol derivatives, and resveratrol oligomers [12]. Finally, proanthocyanidins, also known as condensed tannins, are characterized by a polymerization degree (PD) ranging mainly between 3 and 11, up to 17 and more [13].

Biological properties of functional foods and beverages rich in phenylpropanoids are widely diversified, residing in the antioxidant, antihypersensitive, cardioprotective, antiinflammatory, antimutagenic, and antitumoral activities of these pharmaconutrients. In this view, the positive correlation between high plant food intake, particularly in Mediterranean populations, and low risk of chronic diseases, such as coronary hearth disease, ischemic stroke, and cancer emphasized the importance of fruits and vegetables in the diet [14].

Aroma is a fragrance detectable by smell. In wine, it depends on grape, yeast, fermentation, and oak. In particular, wine aroma ensues from the combining of three different gradations: (i) primary, associated with grape aroma; (ii) secondary, formed during must fermentation; (iii) tertiary, appearing as the wine matures, ages, and undergoes technological treatment [15].

Primary wine aroma is largely due to the presence of isoprenoid monoterpens in grape, above all acyclic linalool, geraniol, nerol, citronellol, homotrienol, and monocyclic a-terpineol, mostly occurring as glycosides. Monoterpenes, major components of essential oils, are C10 representatives of isoprenoids, arising from geranyl diphosphate following the head-to-tail condensation of two isoprene residues [15]. Isoprenoids, or terpenoids, are a huge and diversified group of plant chemicals derived from one simple C5 isoprenoid building unit, isopentenyl pyrophosphate. Sensu lato, isoprenoids are lipids, coming from acetyl-CoA metabolism via hydroxymethylglutaryl coenzyme A (HMG-CoA) synthase and reductase [2, reviewed in 16].

Carotenoids are isoprenoid tetraterpens (C40) accumulated in ripening grape berries. These compounds originate from geranylgeranyl pyrophosphate, following different reactions of C5 unit head-to-tail and head-to-head condensation. Oxidation of carotenoids produces volatile fragments, C13-norisoprenoids. These are strongly odoriferous compounds, such as b-ionone (aroma of viola), damascenone (aroma of exotic fruits), b-damascone (aroma of rose), and b-ionol (aroma of flowers and fruits) [17].

Tetrahydro-b-carbolines are indole alkaloids occurring in grape to a low amount and contributing to its antioxidant power [18]. Actually, these compounds have been firstly detected in fermented foods such as cheese, yoghurt, beer, and

Grape phytochemicals: A bouquet of old and new nutraceuticals for human health 835

Figure 1 Grape phytochemicals: the main phytochemical compounds arise from acetyl-CoA and shikimic acids, via the intermediates mevalonate and aromatic amino acids, respectively. C13-norisoprenoids derive from carotenoid oxidation, while the reaction between indoleamines and aldehydes in wine leads to tetrahydro-bcarbolines.

836 wine, arising from indoleamine (tryptophan) cyclization with carbonyl substrates, aldheydes typically [19]. Additionally, tetrahydro-b-carbolines are synthesized in mammalian tissues via endogenous condensation [20]. In central nervous system, they display a wide spectrum of psychoactive properties: tetrahydro-b-carbolines act as reversible monoamine oxidase inhibitors and benzodiazepine receptor agonists, besides binding to dopamine and imidazoline receptors and inhibiting serotonin (5-hydroxytryptamine, 5-HT) (re)uptake [21]. In addition to the reported psychopharmacological effects, tetrahydro-b-carbolines are potent anticancer agents, being active by different biochemical and molecular mechanisms, namely apoptosis induction and DNA topoisomerase I, II, and cyclindependent kinase inhibition [22].

Melatonin (N-acetyl-5-methoxytryptamine) has been recently discovered in grape [8]. It was long thought to be a neurohormone found exclusively in vertebrates, up to its recent detection in bacteria, protozoans, algae, plants, fungi, and invertebrates [23]. Ever since, melatonin has been found in edible plants, medicinal herbs, and seeds.

The essential amino acid tryptophan is the precursor of all the pineal 5-methoxyindoles, or indoleamines/tryptamines, including melatonin, through the intermediate serotonin and the activity of hydroxyindole-O-methyltransferase [24].

Nevertheless, animals lack the ability to synthesize tryptophan, thus they must obtain it from plant and microbial sources [25]. Besides being produced and secreted by pineal gland in a circadian and seasonal rhythm, melatonin is also synthesized by retina and gastrointestinal tract. Circulating melatonin levels are involved in the regulation of either physiological and pathological conditions, including sleeping, vascular tone, calcium homeostasis, bone turnover, sexual development, immunity, and cancer.

These activities are mediated by binding to G-protein coupled melatonin membrane receptors (MT1, MT2, MT3), diffuse in central nervous tissues, peripheral, and steroidogenic tissues. As well, melatonin directly reduces electrophilic radical species [26], due to its electron-rich aromatic indole ring, and enhances cellular detoxifying enzymes, specifically glutathione peroxidase, glutathione reductase, and superoxide dismutase [27].

What is the melatonin content in plant foodstuffs. . .

As introduced in the former section, melatonin has been detected in different plants and seeds. Medicinal herbs include the major melatonin source for

Iriti and Faoro human, ranging from 1300 to 7000 ng/g in Scutellaria baicalensis (huang-qin), Tanacetum parthenium (feverfew), and Hypericum perforatum (St. Johns wort) [28,29].

Brassicaceae contain higher amount of melatonin than either edible seeds and plants. Its concentration in white (Brassica hirta) and black (Brassica nigra) mustard seeds is 189 and 129 ng/g, respectively, whereas grains contain a lower level of it, from 0.9 to 1.9 ng/g, increasing from barley to rice, oat, and corn. Other seeds significantly rich in melatonin are almond (39 ng/g), sunflower (29 ng/g), fennel (28 ng/g), and green cardamom (15 ng/g) [30–32].

The lowest content of melatonin (lesser than 0.6 ng/g) has been found in vegetables, cucumber, onion, spinach, carrot, tomato, and radish, as well as in fruits, pomegranate, strawberry, pineapple, apple, and banana, with the exception of tart cherry, whose melatonin concentration ranges from 13 to 20 ng/g [30,33–35]. Intriguingly, no indoleamines have been detected in potato, despite the occurrence in this plant of tyrosine/tyramine-derived catecholamines [35,36].

Interestingly, an explanation about the higher melatonin content in seeds, compared with that found in other plant organs, could be the necessity, for a plant, to protect the delicate and lipid-rich tissues of the embryo from oxidative stress [31].

. . .and in grape?

As for other phytochemicals, particularly polyphenols, melatonin content differs to a certain extent among the assayed grapevine cultivars, namely Barbera, Croatina, Cabernet Sauvignon, Cabernet Franc, Marzemino, Merlot, Nebbiolo, and Sangiovese [8]. Nebbiolo and Croatina resulted to have the highest melatonin concentration, 0.9 and 0.8 ng/g, respectively, whereas the lowest level has been detected in Cabernet Franc (0.005 ng/g) [8]. Accordingly, melatonin content is slightly higher than that reported for fruits and vegetables, at least in the melatonin richest grapevine cultivars, although the observed intraspecific variability. Furthermore, the data above reported were recorded from grape skins. Consequently, melatonin concentration in grape seeds may be still higher than that really detected in grape skins, by virtue of its role in seed tissues and the same as for other nutraceuticals [31,37]. In addition, agrochemical treatments can enhance melatonin level in grapevine, as well as its content may be raised in wine following indoleamine synthesis by yeasts [8,38].

Grape phytochemicals: A bouquet of old and new nutraceuticals for human health

Conclusion Generally, plant food pharmaconutritional properties are attributed to its phytochemical potpourri.

At this regard, grape may be the paradigm of the great variety of natural products synthesized and contained in plant tissues. These products, namely, phenylpropanoids, isoprenoids, and alkaloids combined together, contribute to the beneficial effects derived from the large fruit and vegetable consumption.

Melatonin reports in plants are incomplete and fragmentary, thus it is difficult to estimate dietary melatonin intake from fruits and vegetables, in the face of its significant absorption and bioavailability [30,39]. Furthermore, evidences for the beneficial effects of dietary melatonin on chronic diseases are mainly based on laboratory data, necessitating the support of epidemiological studies, as recently highlighted [40]. Thus, a long distance is still to be covered by plant biologists and physicians in that direction.

Last, but not least, melatonin behaves as a prodrug, as lately reported [41]. Its oxidative metabolism produces kynuramines, a class of biogenic amines, mainly in extrahepatic tissues [41]. In liver, cytochrome P450 monooxygenase metabolizes melatonin to 6-hydroxymelatonin, followed by its conjugation to 6-sulfatoxymelatonin and subsequent urinary excretion, whereas gastrointestinal melatonin undergoes a different metabolism, different from monooxygenation [42]. The latter metabolic pathway leads to kynuramines, that are able to improve mitochondria metabolism, act as cyclooxigenase-2 inhibitors and are powerful antioxidants [43,44].

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