role of medicinal plants, herbs, and spices in protecting human health

5
September 1999: (I4S41445 Role of Medicinal Plants, Herbs, and Spices in Protecting Human Health Douglas A. Balentine,Ph.D., Michael C. Albano, M.A., and Muraleedharan G. Nair, Ph.D. The body of knowledge about plants, herbs, and spices and their respective and collective roles in promoting human health is modest. Flavonoids in tea and anthocyanins in tart cherries were pre- sented as examples of how to move forward in understanding active compounds. Dietary com- pounds, their roles in maintaining human health, and their interactions with established nutrients were determined to be short-term research pri- orities. Introduction The growing concerns for general health, chronic disease prevention, and aging have fueled consumer interest in phytonutrients-also referred to as phytoceuticals-which are plant-derived, naturally occurring compounds thought to have curative,preventative, or nutritivevalue.' Consumed in whole foods or as isolated components in supplements, these compounds are a subcategory of the larger group of medical botanicals and provide the basis for the putative functionality of the plants, herbs, and spices in which they are found. Phytonutrients are found in many widely con- sumed h i t s and vegetables. Tea, onions, wine, and apples contain flavonoids. Soy contains isoflavonesand phytoster- ols, and many fits and vegetables contain carotenoids. Phytonutrients have demonstratedfunctionality as antioxi- dants, as well as in enzymemodulation,cell proliferation,and apoptosis. A panel of food scientists, epidemiologists,toxicolo- gists, natural product chemists, and nutritionists was con- vened to address five questions about current knowledge, priorities, and obstacles regarding phytonutrients. Con- sumption of two types of phytonutrients was addressed by two of the panelists. Douglas A. Balentine addressed Dr. Balentine is Manager, Tea Research, and Mr. Albano is Editor, Lipton, Englewood Cliffs, NJ 07632, USA. Dr. Nair is Professor, Department of Horticulture and National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI, USA. the proposed benefits of tea beverage consumption, cit- ing the demonstrated antioxidant activity of flavonoids in tea beverage. Dr. Muraleedharan G. Nair spoke about the active components from aqueous, ethyl acetate, and metha- nol extracts of tart cherries and their apparent anticancer, antioxidant,and anti-inflammatory activities. Current Status of Scientific Knowledge Workshop panelists agreed that there is only a modest body of knowledge about the active compounds in medi- cal plants, herbs, and spices and their respective and col- lective roles in 6romoting human health. There is great interest in determining the role of phytonutrients in pro- moting improved health and well-being and in reducing cancer, cardiovascular disease, and the effects of aging. While there are some data on flavonoids, isoflavones, al- lyl sulfur compounds, and curcuminoids in turmeric, pan- elists agreed that this group of compounds requires rigor- ous study incorporating epidemiology, in vitro and bio- chemical screens, animal efficacy studies, and human in- tervention trials with intermediate and disease endpoints. Without more comprehensive studies, it is difficult to es- tablish a clear position on the use of these compounds for promoting human health. The data on flavonoid com- pounds in tea and tart cherries were cited as examples of how to move forward in understanding the bioactive com- pounds in plants, herbs, and spices. Flavonoids in Tea People are constantly exposed to reactive oxygen species (ROS) such as hydroxyl and peroxyl radicals, superoxide, and singlet oxygen. Although many in number, natural physiologic defenses against oxidative damage are not completely efficient. Chronic exposure to ROS can dam- age DNA, lipids in cell membranes, and functional and structural protein^,^,^ and has been linked to the develop- ment of chronic diseases such as cancer, cardiovascular disease, cataracts, and dementia.46 Vitamin E, vitamin C, and the carotenoids are well-recognized antioxidant nutri- ents and plants containing flavonoids and polyphenols are potent antioxidants. Therefore, many foods contain- Nutrition Reviews", Vol. 57, No. 9 S4 1

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September 1999: (I4S41445

Role of Medicinal Plants, Herbs, and Spices in Protecting Human Health Douglas A. Balentine, Ph.D., Michael C. Albano, M.A., and Muraleedharan G. Nair, Ph.D.

The body of knowledge about plants, herbs, and spices and their respective and collective roles in promoting human health is modest. Flavonoids in tea and anthocyanins in tart cherries were pre- sented as examples of how to move forward in understanding active compounds. Dietary com- pounds, their roles in maintaining human health, and their interactions with established nutrients were determined to be short-term research pri- orities.

Introduction

The growing concerns for general health, chronic disease prevention, and aging have fueled consumer interest in phytonutrients-also referred to as phytoceuticals-which are plant-derived, naturally occurring compounds thought to have curative, preventative, or nutritive value.' Consumed in whole foods or as isolated components in supplements, these compounds are a subcategory of the larger group of medical botanicals and provide the basis for the putative functionality of the plants, herbs, and spices in which they are found. Phytonutrients are found in many widely con- sumed h i t s and vegetables. Tea, onions, wine, and apples contain flavonoids. Soy contains isoflavones and phytoster- ols, and many f i t s and vegetables contain carotenoids. Phytonutrients have demonstrated functionality as antioxi- dants, as well as in enzyme modulation, cell proliferation, and apoptosis.

A panel of food scientists, epidemiologists, toxicolo- gists, natural product chemists, and nutritionists was con- vened to address five questions about current knowledge, priorities, and obstacles regarding phytonutrients. Con- sumption of two types of phytonutrients was addressed by two of the panelists. Douglas A. Balentine addressed

Dr. Balentine is Manager, Tea Research, and Mr. Albano is Editor, Lipton, Englewood Cliffs, NJ 07632, USA. Dr. Nair is Professor, Department of Horticulture and National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI, USA.

the proposed benefits of tea beverage consumption, cit- ing the demonstrated antioxidant activity of flavonoids in tea beverage. Dr. Muraleedharan G. Nair spoke about the active components from aqueous, ethyl acetate, and metha- nol extracts of tart cherries and their apparent anticancer, antioxidant, and anti-inflammatory activities.

Current Status of Scientific Knowledge

Workshop panelists agreed that there is only a modest body of knowledge about the active compounds in medi- cal plants, herbs, and spices and their respective and col- lective roles in 6romoting human health. There is great interest in determining the role of phytonutrients in pro- moting improved health and well-being and in reducing cancer, cardiovascular disease, and the effects of aging. While there are some data on flavonoids, isoflavones, al- lyl sulfur compounds, and curcuminoids in turmeric, pan- elists agreed that this group of compounds requires rigor- ous study incorporating epidemiology, in vitro and bio- chemical screens, animal efficacy studies, and human in- tervention trials with intermediate and disease endpoints. Without more comprehensive studies, it is difficult to es- tablish a clear position on the use of these compounds for promoting human health. The data on flavonoid com- pounds in tea and tart cherries were cited as examples of how to move forward in understanding the bioactive com- pounds in plants, herbs, and spices.

Flavonoids in Tea People are constantly exposed to reactive oxygen species (ROS) such as hydroxyl and peroxyl radicals, superoxide, and singlet oxygen. Although many in number, natural physiologic defenses against oxidative damage are not completely efficient. Chronic exposure to ROS can dam- age DNA, lipids in cell membranes, and functional and structural protein^,^,^ and has been linked to the develop- ment of chronic diseases such as cancer, cardiovascular disease, cataracts, and dementia.46 Vitamin E, vitamin C, and the carotenoids are well-recognized antioxidant nutri- ents and plants containing flavonoids and polyphenols are potent antioxidants. Therefore, many foods contain-

Nutrition Reviews", Vol. 57, No. 9 S4 1

ing these compounds are excellent sources of phytochemi- cal antioxidants that may factor in oxidative defense and disease pre~ention.~-*~

Dietary factors play a major role in the development of chronic diseases. The U.S. government actively en- dorses increased consumption of fruits and vegetables to improve public health. This position is based on epide- miologic data, but the exact components of plants respon- sible for the health benefits have not been identified. Al- though fiber, vitamins, and minerals are presumed to be important, other food components most likely provide pro- tection against chronic diseases as well.

Tea is a good source of free radical-scavenging anti- oxidants." In fact, tea's ability to scavenge free radicals is so well accepted that researchers now routinely use tea components as antioxidants. Tea is thought to have greater antioxidant capacity than most vegetables, and is more potent than vitamins C, E, and p-carotene. Tea compo- nents are bioavailable, including those shown to have powerful antioxidant functions.I2

Tea beverage, prepared by infusing the laves of Camellia sinensis, contains a number of biologically ac- tive components not usually associated with basic nutri- tion. There are three types of manufactured tea: black, green, and oolong. Black tea is the type of tea typically consumed in the United States, Europe, Africa, and India. Black tea is made by crushing and drying fresh tea leaves to bring about a "fermentation" prior to final processing. Green tea, which is consumed typically in East Asian coun- tries, is created by rapidly processing the fresh leaves, which prevents fermentation. Oolong tea is partially fer- mented.13

All tea beverages are rich in flavonoids. Flavonoids scavenge free radicals and act as antioxidants by either delocalizing electrons and forming intramolecular hydro- gen bonds, or by rearranging their molecular structure. Free copper and iron, which catalyze formation of ROS in vivo and are used to generate free radicals in some test systems, are chelated by flavonoids."

Compounds in Tart Cherries It is generally believed that many common foods contain non-nutrient components such as flavonoids and antho- cyanins, which are considered to reduce the incidence of chronic diseases.'"I8 Tart cherry is one such food touted for its various health benefits. In order to evaluate the anecdotal claims, Dr. Nair's laboratory has investigated the active components from aqueous, ethyl acetate, and methanol extracts of Montmorencylg-zz and Balaton'" tart ~ h e r r i e s ~ ~ , ~ ~ and determined their anticancer, antioxidant, and anti-inflammatory a c t i v i t i e ~ . ~ ~ . ~ ~

Three anthocyanins, [cyanidin-3-(2"-0-P-D-gluco- pyranosyld ' '-0-a-L-rhamnopyranosyl- P-D-glucopyrano- side], [cyanidin-3 -( 6"-0-a-L-rhamnopyranosyl- P-D- glucopyranoside] and [cyanidin-3-0-P-D-glucopyrano-

side] were identified in the aqueous extracts of both Mont- morency and Balaton'" tart cherries by antioxidant assay- directed fractionation and p u r i f i c a t i ~ n . ~ ~ However, Balaton'" tart cherries contained approximately six times more anthocyanins than Montmorency tart cherries.z3

The anthocyanins and their aglycones-cyanidin- were further tested for antioxidant activity using Fez+-in- duced lipid peroxidation. The antioxidant activities of an- thocyanins and cyanidin are comparable to the commer- cial antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) and are superior to vita- min E at 2 pM concentrations. The number of sugar moi- eties at the C, position is an important factor in the varia- tion of antioxidant activity observed for an tho cyan in^.^^

The anti-inflammatory activities of anthocyanins and, cyanidin were assayed on prostaglandin endoperoxide H synthase-1 (PGHS-1) and -2 (PGHS-2) enzymes. Results suggested that anthocyanins did not show PGHS-1 and PGHS-2 inhibitory activities. However, the aglycone cya- nidin demonstrated PGHS- 1 and PGHS-2 inhibitory activi- ties at IC,, values of 90pM and 60 pM, respectively. The positive controls-aspirin, ibuprofen and naproxen-had IC,, values of 1050, 1 1, and 25 pM, respectively, against COX-1 enzyme.z4 The anthocyanins, which are not active in in vitro assays, can be metabolized to cyanidin in bio- logical systems and hence can act as an anti-inflammatory agent. The akhocyanins are the most abundant class of compounds in cherries and may have the potential to sub- stantiate anecdotal claims associated with them, such as the reduction of arthritic and gout related pain and inci- dence of cardivascular diseases.

From the ethyl acetate extract of Balaton'" tart cherry, three novel compounds- 2-hydroxy-3-(o-hydroxyphenyl) propanoic acid, 1 -(3 ', 4'-dihydroxycinnamoy1)-cyclopenta- 2,5-diol, and 1 -(3 ', 4'-dhydroxycinnamoyl)-cyclopenta-2,3- diol-were identified by 'HNMR, I3C NMR, DQCOCY, HMQC, FABMS, and EIMS experiments. The inhibitory activities of lipid peroxidation of 1 -(3 ',4'-dihydroxy- cinnamoyl)-cyclopenta-2,3-diol and 1-(3 ',4'-dihydroxy- cinnamoyl)-cyclopenta-2,5-diol were 79% and 75%, respec- tively, at 20 pM concentrations. However, 2-hydroxy-3- (o-hydroxyphenyl) propanoic acid showed no activity at 100 pM. The antioxidant activities of these compounds were compared with caffeic acid analogues; it was con- cluded that the 3, 4-dihydroxy functionality on the aro- matic ring is essential for the antioxidant activities of caf- feic acid analogues. The smaller the ester group, the bet- ter the antioxidant activity. These phenolic compounds did not show anti-inflammatory activity when tested at 1000 pM concentrations.

From the methanol extract of Balaton'" tart cherry, five flavonoids--5,7,4'-trihydroxyflavanone, quercetin 3- rhamnoside, kaempferol3- 6 "-0-a-L-rhamnopyranosyl-P- D-glucopyranoside, rhamnazin 6"-O-a-L-rhamno- pyranosyl-P-D-glucopyranoside, and 5,8,4'-trihydroxy-

S42 Nutrition Reviews@, Vol. 57, NO. 9

6,7-dimethoxyflavone-and two isoflavonoids, 5,7,4’- trihydroxyisoflavone and 5,7,4‘-trihydroxyisoflavone 7- glucoside, were identified by spectral meth0ds.2~ Research- ers found rhamnazin 6”-O-a-L-rhamnopyranosyl-p-D- glucopyranoside and 5,8,4‘-trihydroxy-6,7-dimethoxy- flavone in tart cherries for the first time and 5,8.4’-trihy- droxy-6,7-dimethoxyfalvone was found to be the most ac- tive antioxidant phenolic compound isolated from Balaton’” cherry. The antioxidant activity of 5,8.4’-trihy- droxy-6,7-dimethoxyflavone is better than that of tert- butylhydroquinone (TBHQ) and butylated hydroxytolu- ene (BHT) at 10 pM ~oncentrations.2~

These compounds were further tested for WGSH- 1 (COX-1) inhibitory activity and compared with structur- ally related compounds. Genistein is the most active COX- 1 inhibitor among the compounds isolated from Balaton‘“ tart cherry. In isoflavonoids, the OH groups at C4,’ C5, and C, are the essential functionality for COX- 1 inhibitory ac- tivity. In the case of flavonoids, C,-C, unsaturation deter- mined the coplanarity of the heteroring and is essential for the increased COX- 1 inhibitory activity. Similarly, tke OH groups at C,’ and C, hydroxyl groups are also impor- tant factors for COX-1 inhibitory activity. Flavonoids with high number of substitutions in ring A, such as 5,8,4‘- trihydroxy-6,7-dimethoxyflavone, did not exhibit COX- 1 inhibitory activity. It is possible that if the phenyl g r o u p ring B-is substituted at C,, the COX-1 inhibitory effect may be enhanced.

Our study indicated that a number of compounds present in tart cherries have antioxidant and prostaglan- din endoperoxide H synthase (COX) enzymes inhibitory activities in vitro. The antioxidant or free-radical scaveng- ing action and the enzyme inhibitory actions of anthocya- nins and flavonoids present in tart cherries could account for many other pharmacologic activities, such as antialler- gic, antiviral, anticancer and anticarcinogenic activities, and the prevention of cardiovascular disease and aging. Hence, it can be hypothesized that consumption of cher- ries containing these compounds might be beneficial in protecting humans against various chronic diseases.

In order to verify these in vitro results, extensive hu- man trials using cherries and cherry extracts should be carried out. Similarly, bioavailability of these cherry com- pounds in humans should be studied to determine whether the mechanism of activity is similar to that demonstrated in our in vitro studies.

and preparation methods as well as the plant matrix within which the phytocompounds are present. Another high priority is the development of appropriate in vitro and in vivo bioassays for whole foods and food matrixes. The Oxygen Radical Absorbance Capacity (ORAC) research on fruits and vegetables at the Jean Mayer Human Nutri- tion Research Center on Aging at Tufts University is a good example of appropriate new methodologic develop- ment, and more of this kind of work is needed. Areview of the Tufts ORAC data will soon look at correlation to changes in plasma antioxidant status, and more types of assays to look at other health endpoints are needed as well.

What Are the Technical Barriers to Obtaining This Additional Information?

Discussion of Crop Profiling and Biomarkers Panelists identified a need for a better understanding of the respective phytonutrient profiles of food crops from the complementary compositional and “fingerprint” points of view. It was also determined that biomarkers for im- proving health-as opposed to those for curing or pre- venting disease-should be further developed. Biomarkers are also needed so that data on nutrient phytochemical intake can be correlated to epidemiology and disease risk. Biomarkers were-the specific focus of one of the other workshops in this symposium.

Human Health and Consumption While panelists agreed that human models and methods should be examined from the points of view of antioxi- dants, immune function, coronary heart disease and can- cer, the aspects of overall health and well-being must be addressed as well. Food systems should also be examined from an epidemiologic point of view in terms of how the diet and its components interact.

Although the marketing of phytonutrients is already way ahead of the science, consumers are looking for in- formation now. Panelists discussed the best ways to com- municate the science to consumers, including the use of a “five-a-day” idea, based on a portfolio of foods that pro- vides a variety of phytonutrients of interest. However, because specific agencies and departments are charged with communicating this information to the public, this clearly was not the focus of this workshop.

What Are the Immediate Priority Research Topics?

What Additional Knowledge Is Needed to Move the Field Forward?

One of the first priorities as we move ahead is chemical characterization of the phytonutrients in our food and agricultural products. This characterization should include data on the availability of phytonutrients in foods, taking into consideration the various effects of food processing

Emphasis on Whole Foods In studying the effects of phytonutrients, emphasis should be on whole foods and dietary consumption habits rather than limited to individual components of selected foods.

Nutrition Reviews@, Vol. 57, No. 9 s43

Moreover, when specific foods within the diet are stud- ied, more attention must be focused on the intercultivar and intervarietal differences of plants if the study of the effects of phytonutrients is to be meaningful. As an initial approach, human subjects would consume foods with known (phyto)chemical profiles and bioendpoints of ac- tivity would be measured using in vivo and in vitro as- says. The panelists concurred that determination of the effect of any individual component is peripheral to the short-term priority of understanding health endpoints for foods as they are consumed.

Panelists also discussed how agricultural processes influence phytonutrient content, and whether varieties of agricultural products with known phytonutrient profiles should be engineered or selected.

Model Systems One panelist questioned the relevance of the ORAC find- ings to human physiology, alerting us to the possibility of publishing misleading data that could be harmful to the consumer. His recommendation was a to use quick sctling assay with relevance to human physiology. Another pan- elist thought the model systems currently in use for phytonutrient evaluation seemed as cumbersome and as complicated as the substances being studied. Giving the example of geneticists, who use easy-to-manipulate model systems, he asked panelists about ways to approach the selection of model systems and possible directions.

In response, carrots were suggested as a good model system because unlike spinach, they can be engineered or manipulated in tissue culture. It was also recommended that because model systems are topic-dependent, seg- mentation, or having one or two model systems for each aspect of phytonutrients and human health, be imple- mented. Participants suggested that model systems for discovery of new crops or phytonutrients should be rapid; however once a phytonutrient is discovered, a more spe- cific in vivo model should be used.

Phytonutrient Interactions Panelists determined that it is important to understand the synergies and interactions of food phytonutrients from various sources, including spices and botanicals used as food ingredients. It was determined that drugs or non- food medicinals are a much lower level priority. The panel deemed it necessary to determine safe and efficacious lev- els of intake for acute studies versus chronic consump- tion in an attempt to evaluate safety, toxicity, and upper limits of selected phytonutrients.

After extensive discussion, panelists determined that a multidisciplinary approach to maximize available re- sources within the research community is needed. One panelist noted that development in core labs is necessary since expertise in every aspect of phytonutrients is unre- alistic because the area is too complicated.

Background on Food Composition The food composition laboratory within the Agricultural Research Service (ARS), located in Beltsville, was estab- lished by Edith Weir and Will Gortner in the early 1970s. At that time, there was a need for the development of analytic methodologies for measuring nutrients in foods. The laboratory was put in place in 1975 with the specific mission of developing analytic methodologies that could be off-loaded to industry and other places for measuring nutrients in foods. That mission continues to this day and is seen as complementary to the mission of the National Institutes of Health, which does not place a high priority on the funding of methods development. The Western Regional Research Center, which is also part of the ARS system, also contributes to the development of methods appropriate to the newer lines of investigation that char- acterize plant compounds and their bioactivity.

Absorption, Metabolism, and Endpoints The question was posed about the best way to move for- ward in understanding the absorption of phytonutrient compounds from foods or processed foods, and how that process influences the likelihood that these compounds will be bioactive in humans. Dr. Prior commented that much time could be spent looking at absorption and metabolism of compounds ar components in foods. However, if the panel agreed to a functional endpoint-even in human studies-then these foods could be fed resulting in a posi- tive benefit in that endpoint. Dr. Prior gave the example of rat studies in Dr. James Joseph’s lab, where the rats showed some responses in neurotransmitter systems after being fed extracts from fruits and vegetables. Prior went on to say that the quantity of absorption is unknown, but that enough was absorbed so as to have an effect on the end tissue.

Lachance contributed some background on medici- nal plants, herbs, and spices, stating that the value of the supplement business was $10 billion and the value of the nutraceutical business is $60 billion with 7-8% annual growth. He cited the addition of nutraceuticals to pet food and cosmetics in the context of annual growth.

Prior commented that a focus should be on sound scientific information to justify the claims being made. Lachance stated that the demand exists for botanicals and that his lab was able to fund twelve out of a pool of thirty farmers to grow botanicals. As botanicals are gaining in popularity and are increasingly considered “value added,” farmers are switching from growing conventional crops to growing botanicals to augment their income. Lachance thought that the United States Department of Agriculture and other institutions should advise farmers, who com- prise 2-3% of the population, about growing new crops as well as conventional ones.

In terms of the nutrient data bank, the question was raised as to how much emphasis should be placed on

s44 Nutrition Reviews@, Vol. 57, No. 9

analyzing dietary spices and herbs, which are currently underrepresented, for either research purposes or dietary survey purposes. Kohlmeier added that in terms of mea- suring non-nutrients for inclusion in the food composi- tion database, new areas of interest-such as breast can- cer drug interactions-should be investigated in lieu of polishing and refining existing areas.

What Are the Priority Research Topics Long- Term?

Effects of Individual Components Determination of the effect of any individual component was thought by the panelists to be peripheral to the short- term priority of understanding health endpoints for foods as they are consumed.

What Is the Role of the Government in Phytonutrient Research and How Does It Complement Privately Sponsored Reseatch?

Panel Mandates The question was raised as to whether or not academia and government should be responsible for explaining mechanisms. A general opinion of the panel was that the government is uniquely well-positioned to consider the wide field of interactions among foods, diet composition, nutrients, and botanicals, and thus this should be a prior- ity of federal research programs

The overall conclusion of the panel with regard to the unique role of the federal government was that the diet, the composition of the diet, and sustaining a healthy food supply are priorities. Compounds that become part of the diet, their roles in maintaining health, their interactions with established nutrients, and how they all work together were also considered to be priorities.

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