1668.81 (78.88)

1665.02 (92.51)

1038.51 (52.49)

1820.75 (91.87)


a Maffei and Scannerini, 1999; b Maffei et al., 1999; c Maffei and Scannerini, 2000.


a Maffei and Scannerini, 1999; b Maffei et al., 1999; c Maffei and Scannerini, 2000.

temperature increases the rate of enzyme activity increases up to 40—50 °C, according to the enzyme. Above 50 °C most plant enzymes are inactivated and even permanently damaged (Cseke and Kaufman, 1999). During seasonal changes, temperature may play a major role in the quality and quantity of bioactive compound produced. In temperate regions, a hot summer may not be accompanied by a suitable rain regime, thus leading to water stress and growth reduction. On the other hand, high temperatures and heavy rain generate high humidity which may trigger pathogen growth and disease spread.

Developmental stages are another important factor involved in bioactive compound quality and quantity. Some compounds such as terpenoids accumulate in secretory structures (see above) which differentiate in the early stages of leaf development. The density of these structures is very high in young leaves and tends to decrease with leaf development (Maffei et al, 1989). In many species, anthocyanin production is often more evident in young leaves than in old ones. Capsules of opium poppy produce more alkaloid than any other part of the plant, whereas roots of some medicinal plants produce metabolites that are present only in small amounts in leaves. The number of investigations related to changes of bioactive compounds with regard to plant part and development is extraordinarily great (Bernath, 1986). Functional relationships exist between ontogenetic change and development and between development and accumulation of bioactive compounds. Morphogenesis (the acquisition of shape or form) and photomorphogenesis (light-dependent morphogenesis) are the sum of patterns of both cell division and cell expansion, which in turn differentiate owing to the turning on or off of genes (gene expression) and the ensuing alteration of the cell's complement of enzymes and structural protein.

Temperature, light, water, nutrients, plant development, pathogen and herbivore attack, all affect the quantity and quality of bioactive compounds and this has to be taken into consideration when secondary metabolites are present in dietary supplements of plant origin. The growth conditions of a certain herb (place of growth, fertilizers used, environmental conditions, etc.) are important factors affecting the presence and the content of a compound.

Standardization of dietary supplements of plant origin

The approach for drug development from plant resources depends on the aim. Different strategies will result in a herbal medicine or in an isolated active compound. However, apart from this consideration, the selection of a suitable plant for a pharmacological study and the standardization of the process are very important and decisive steps (Rates, 2001). There are several ways in which this can be done, including chemical content, toxicity, randomized selection, biological and physiological studies or a combination of several criteria (Ferry and Baltassat-Millet, 1977; Soejarto, 1996; Williamson et al, 1996).

Phytomedicines are freely marketed and, in underdeveloped or developing countries, the use of medicinal plants is widely accepted. This can result in toxic accidents from the use of plants as food or for therapy or from accidental ingestion by children or animals. Toxicity can result from highly concentrated doses or from the state of conservation of plants and the form of use (Rates, 2001). Among the various types of registered cases, we can find: (A) accidents due to mistakes of botanical identification (use of a wrongly identified plant is common, as is the substitution of different plants for the same indication) (Pereira, 1992); (B) intoxication by popular remedies (popular remedies, made without legal authorization and sold by herbalists or even prescribed by religious leaders for use in rituals, have often resulted in toxic symptoms immediately after ingestion or later) (Rates, 2001); (C) accidents with cardiotonic plants: plants with a high content of cardiac glycosides, such as Nerium oleander, Thevetia peruviana, Gomphocarpus fruticosos and Calotropis procera, are used as decorative plants and have caused a number of domestic accidents involving children and animals (Rates, 2001); (D) plants that interfere with conventional pharmacological therapy (see chapter by Cott); (E) other toxic plants.

Food contains nutrients which are not only capable of meeting caloric and general metabolic needs but can also affect specific metabolic functions which can either initiate or retard the process of degeneration of the cells and tissues of the human body (Burn and Kishore, 2000). Endangering consumers' (patients') health by changing the product's quality, whether deliberately or otherwise, is a major concern of all regulating authorities. Therefore, any change to the process has to be proved to yield a comparable product. If the product's characteristics have been modified, the resulting product would be considered to be a new product and have to be evaluated fully (Doblhoff-Dier and Bliem, 1999).

The above issues clearly point to the fact that one of the major problems in dealing with dietary supplements of plant origin is the definition of reference standards. Different types of standards have been proposed; among these are: (a) authenticated reference plant material (ARPM); (b) powdered plant material; (c) purified 'active' chemical constituents; and (d) plant extract (powdered or semi-solid).

a ARPM requires a positive identification that has to be at different levels such as histological and taxonomical; to this end, plant organs or tissues have to be certified by specialists such as taxonomists, botanists, histologists and pharmacologists. ARPM requires reference material to enable us to detect adulteration with other plant species of the same genus or other foreign organic matter. In order to establish ARPM there is the need for a careful selection of seeds, planting and irrigation as well as harvesting at the right time. Furthermore, the preparation of a herbarium is required, as is the consequent identification, certification and storage of plants.

b Powdered plant material is prepared from dried plant parts (e.g. leaves, flowers, stems, roots). Positive identification is done by comparison with the sample under test by using analytical techniques such as TLC (thin-layer chromatography), HPLS (high-performance liquid chromatography), LC-MS (liquid chromatography — mass spectrometry) and GC-MS (gas chromatography — mass spectrometry).

c Issues related to purified chemical constituents are mainly: purity of compounds, their stability, their availability or replaceability, the quantity supplied and the relative cost.

d Plant extracts must be stable, the quality of raw material must be high, and the solvent(s) used and the ratio of solvent(s) to plant material has to be known, as well as the consistency in composition.

According to the Consumer Healthcare Products Association (the national trade association representing US manufacturers and distributors of non-prescription, over-the-counter medicines and dietary supplement products), dietary supplements have been attacked for not meeting quality standards. However, while some of these allegations may seem accurate, there has been a concerted effort of the industry and governmental organizations to establish standards for dietary supplements. Surely, the physiology and biology of the living plant cannot be ignored when quality and quantity of products are to be certified and standardized in herbal remedies and dietary supplements of plant origin. Through partnership(s) with private, professional, academic and governmental groups one can achieve the goal of establishing quality standards for dietary supplements of plant origin.

Based on results of national opinion surveys, including the views of both users and non-users of supplements, Blendon and co-workers (2001) found that a substantial percentage of Americans surveyed reported that they regularly take dietary supplements as a part of their routine health regimen. Usually they do not discuss the use of dietary supplements with their physicians because they believe that the physicians know little or nothing about these products and may be biased against them. Many users felt so strongly about the potential health benefits of some of these products that they reported that they would continue to take them even if they were shown to be ineffective in scientifically conducted clinical studies. The majority of Americans surveyed want the Food and Drug Administration to review the safety of new dietary supplements prior to their sale, to provide increased authority to remove from sale those products shown to be unsafe, and to increase government regulation to ensure that advertising claims about the health benefits of dietary supplements are true (Blendon et al, 2001).

The extent of concern about safety and efficacy of herbal remedies is widened by recent consideration of the healing properties not only of herbs but of plant foods in general. Burn and Kishore (2000) propose a new name — 'vitalins' — to those molecules of dietary origin which help preserve vital functions and, thus, vitality of the body. 'Anti-vitalins' are those molecules that have the opposite effect, i.e. one of accelerating the degenerative process. Vitalins are therefore a class of nutrients and anti-vitalins are a class of anti-nutrients. Functional foods are foods containing one or more of these vitalins or foods depleted of anti-vitalins. They are more functional in their ability to meet metabolic needs of either the whole body or specific organs of the human body, in a context which includes vitality in addition to general metabolic activities (Burn and Kishore, 2000) (see Chapter five for further details).

While scientists continue to dissect food and determine its molecular components that deliver nutritional and health benefits at an unprecedented pace, there is a growing need for science-based regulations that will help to distinguish science-based nutrition and disease prevention from quackery and anecdotal stories (Tyler, 1999). Thus, standardization is not just an analytical operation and does not end with the identification and assay of the main active principles. Standardization signifies the body of information necessary to guarantee not only a constant chemical composition of herbal medicines, but also an equal efficacy (Capasso et al, 2000).

Why are bioactive plant compounds produced?

The last question to be answered in this section is why plants produce bioactive molecules. Our anthropocentric view of herbal remedies leads us to think that plants evolved their ability to produce secondary metabolites not for their own use, but to be used by animals and humans to heal pains and diseases. However, plants appeared more than 400 million years ago, long before humans, during the Silurian Period. During the Permian, plants and animals slowly changed and gymnosperms and Cycadaceae took the place of Lycopodales and tree-ferns. At that time, probably half of all insects were feeding on plants. Most herbivorous insects were present in the Palaeozoic as well as during the Mesozoic. Over the ages plants and their predators have evolved several strategies to survive. The tolerance of plants to herbivory reflects the degree to which they can regrow and reproduce after damage from herbivores. Auteco-logical factors, as well as the influence of competitors and mutualists, affect the level of plant tolerance. Recent work indicates that there is a heritable basis for tolerance and that it can evolve in natural plant populations (Strauss and Agrawal, 1999). Although tolerance is probably not a strict alternative to plant resistance, there could be inter-and intraspecific tradeoffs between these defensive strategies.

In general, the success of plants derives in part from their highly evolved defence systems, which have allowed them to withstand interspecific competition as well as herbivore and pathogen predation (Phillips and Croteau, 1999). From a biochemical point of view, because multiple pathways are elicited during attack by either herbivores or pathogens, a clear dichotomy between pathogen- and herbivore-specific defence pathways does not always exist (Felton and Korth, 2000). The contemporary evolution of plants in producing chemical defences and herbivores in counterattacking them has been termed co-evolution, as we will discuss in the next subsection.

118 Massimo Maffei Co-evolution

Ehlrich and Raven (1964) were among the first researchers to introduce the theory of biochemical co-evolution, in which bioactive plant metabolites are biosynthesized as a consequence of host-plant utilization by herbivores. The advent of this theory, along with the suggestions already made half a century ago by Fraenkel (1959), have changed the view of secondary metabolites from waste products to bioactive molecules. The core of the theory is centred upon the concept that a systematic evaluation of plants fed upon by herbivores leads to the conclusion that bioactive plant metabolites play the leading role in determining patterns of utilization. This concept allows us to explain the vast and irregular distribution of secondary plant metabolites in the plant kingdom. Plants, via occasional mutations and recombinations, have produced an array of chemical compounds not necessarily linked to primary metabolism. Some of these compounds have been successful in reducing or deterring insect and herbivore feeding and for this reason have been 'conserved', whereas others did not find a metabolic and functional 'place' in the evolutionary path of some species and for this reason have been genetically deleted. On the other hand, herbivores have faced up to plant defences and have evolved ways to detoxify them. Individuals able to feed chemically defended plants have survived, whereas others, unable to feed or deterred by plant compounds, had to move to other plants in search of food or die. This animal—plant co-evolutionary behaviour eventually led to insect discrimination between plants in feeding, with many herbivores feeding on a small number of related species belonging to the same genus, tribe or family. The toxicity of some compounds to insects may be exerted by individuals sharing the same biochemical machinery but with different anatomy and morphology, while plants sharing the same morphology or anatomy may produce different chemical weapons. As we observed above, plants can use constitutive and/or induced bioactive compounds, depending on the environmental pressure imposed by herbivores, predators and abiotic factors (Harborne, 1993).

The continuous pressure of herbivores upon plants and the ensuing plant responses and herbivore counterattacks have generated the sea of metabolites that Mother Nature offers and that humans and animals have learned to use. To this picture we may add the environmental pressures caused by changing weather conditions, water and nutrient availability, light intensity and quality (UV-A and UV-B irradiation) and, more recently, air, soil and water pollution caused by human activity.

Another way plants have evolved bioactive compound synthesis is through multiple interactions with herbivores. Plants respond to an initial attack by herbivores and pathogens by increasing their levels of defence (Agrawal, 1998). For example, volatile compounds that are attractive to natural enemies of herbivores are hypothesized to be an evolved response to herbivory. Although the net costs or benefits in plant performance of such induced volatile responses have not been identified, intricate and highly specific interactions between constituents of herbivore saliva and plant responses provide circumstantial evidence of their importance. This kind of interaction of plants, herbivores and predators is called tri-trophic interaction. Studies of tri-trophic interactions aim to identify them, understand their mechanistic basis and document their consequences. Ultimately manipulating these interactions may result in better pest control and the reduced use of pesticides (Agrawal, 2000). In terrestrial environments, strong trophic interactions are modified by the chemistry, morphology and behaviour of each organism involved. Plants recruit natural enemies of herbivores using volatiles.

Plants must discriminate between different environmental challenges in order to optimize the allocation of their resources to growth, defence and reproduction. Phytophagous insects display a great diversity of feeding modes and life histories, and it is important for plants to distinguish between insects that have different fitness consequences for the plant (Baldwin et al., 2001). The essential constituents of these interactions, ranging from herbivore saliva to plant hormones and regulatory enzymes, are now being isolated, and their genes cloned. It is not known whether plants that are infested with microbial diseases or nematodes attract or facilitate natural enemies of these plant parasites. Such interactions are probably abundant, yet their natural history and potential application have not been explored (Agrawal, 2000).

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