TOPIC 2B THE ADME PROCESS AND HEALTH BENEFITS AND APPLICATIONS.pptx

Nutraceuticals

1. THE ADME PROCESS AND HEALTH BENEFITS AND APPLICATIONS OF PHYTOCHEMICALS BY ANTHONY MENSAH ASARE

2. TABLE OF CONTENT INTRODUCTION ADME PROCESS TERPENES POLYPHENOLS CAROTENOIDS GLUCOSINOLATES LECTINS HEALTH BENEFITS OF PHYTOCHEMICALS CONCLUSION REFERENCES

3. INTRODUCTION In general, phytochemicals are secondary plant metabolites; that is, substances synthesised by plant cells, but which serve some function beyond the primary needs of the cell, and contribute to the survival of the whole plant as a functional organism. Some phytochemicals confer colour or scent, others act as signalling molecules, either within the plant itself, or in interactions with other organisms, and many are believed to function as natural pesticides. Some of these substances are pharmacologically active, whilst others are either profoundly unpalatable or highly toxic.

4. INTRODUCTION-2 Clearly, if phytochemicals are to be of benefit to human health, they must reach their target tissues in physiologically significant quantities. Some secondary plant metabolites may act entirely within the lumen of the alimentary tract, perhaps by functioning as quenching agents for free radicals, or by interacting directly with gut epithelial cells, without ever crossing the intestine and entering the blood stream. This type of localised activity could perhaps account for protective effects of some fruits, vegetables or functional foods against digestive diseases such as gastric or colorectal cancer, but if phytochemicals play a larger role in human health, they must first cross the gut and enter the circulation in active forms.

5. THE ADME PROCESS One very important characteristic of phytochemicals that distinguishes them from organic micronutrients is the lack of any evidence for specialized adaptations of the human body that might serve to maximize their absorption and delivery to the tissues. Indeed, many phytochemicals are transferred only sparingly across the intestinal mucosa, and those com pounds that do cross the intestinal surface in significant quantities tend to be rapidly metabolised by the Phase II enzymes, which convert potentially toxic molecules to water soluble conjugates.

6. THE ADME PROCESS -2 Much of this metabolism occurs in the gut mucosa, and a large fraction of the products are actively secreted back into the gut lumen (Petri et al., 2003), there to be either metabolised further by the gut microflora, or lost in the faeces . In many cases, any unmetabolised compounds that do enter the circulation undergo metabolic conversions during their first pass through the liver, so that it is the modified forms that reach the target tissues, not the native compound found in the plant.

7. TERPENES Chemically modified terpenes are very common in nature, and are termed terpenoids or isoprenoids. Terpenes and their derivatives occur widely in the plant kingdom, often as components of resins and essential oils. They are often coloured or pungently scented, and they enter the human food chain as constituents of citrus fruits, or as aromatic food ingredients, such as ginger, cinnamon and cloves. The carotenoids are a particular class of terpenoids, based on eight isoprene units. Because of their highly lipophylic behaviour , terpenes and their derivatives are likely to cross biological membranes readily by passive diffusion.

8. TERPENES-2 However, their solubility in the aqueous phase of the gut lumen will be low; and their bioavailability will probably depend upon emulsification and partioning into the micellar phase during gastrointestinal lipid digestion. Terpenes are rapidly absorbed via the pulmonary route due to their volatile nature, leading to quick systemic circulation. Their lipophilic properties enable penetration through the stratum corneum, making them suitable for dermal formulations. Some terpenes act as skin penetration enhancers for drugs.

9. TERPENES-3 Most terpenes show moderate to high binding to plasma proteins, affecting their distribution. Due to their lipophilic nature, terpenes tend to accumulate in fat-rich tissues, the liver, and the brain (crossing the blood-brain barrier). This is particularly relevant for terpenes with neuroactive properties. Terpenes undergo extensive cytochrome P450 enzyme-mediated metabolism in the liver. Common metabolic pathways include hydroxylation, epoxidation, and oxidation. Example: Limonene is metabolized to perillyl alcohol, carveol , and carvone. Further metabolism occurs via glucuronidation and sulfation, making terpenes more water-soluble for excretion.

10. TERPENES-4 Water-soluble terpene metabolites (e.g., glucuronide and sulfate conjugates) are excreted in urine. Non-metabolized or less polar terpenes are eliminated via bile and excreted in feces. Some volatile terpenes (e.g., limonene, pinene) are eliminated unchanged through the lungs, contributing to their characteristic aroma in breath.

11. POLYPHENOLS Much of the complexity of the problems associated with the ADME of phytochemicals in general can be judged from the growing literature on the absorption and metabolism of food-borne polyphenols. Amongst this huge group of food-borne substances, the anthocyanins and flavanols have received particular attention. Anthocyanins are a large group of phenolic compounds found abundantly in fruit juices, berries of various types, and wine. Manach et al. (2005) reviewed published data on the absorption and metabolism of anthocyanins in humans.

12. POLYPHENOLS-2 From most food sources, only a very small fraction is absorbed, that the small amount of absorption that does occur takes place very rapidly in the stomach and upper intestine, and that excretion of the absorbed fraction is rapid and efficient. In most human bioavailability studies, the administered doses were in the range of hundreds of milligrams, and resulted in peak plasma concentrations in the 10–50 nmol/L range. The average bioavailability of the anthocyanins has been reported in many studies to be less than 1%. Unlike other polyphenols, unmetabolised anthocyanin glycosides are often detected in blood and urine, but there is evidence that anthocyanin glucuronides and sulphates are unstable in urine.

13. POLYPHENOLS-3 Flavanols are also present in plants as a mixture of water-soluble glycosides, and this is also the form in which they are released into the alimentary tract during digestion. Another aspect of polyphenol metabolism that is poorly understood, but should not be neglected, is the large proportion of the ingested dose that remains in the gut lumen, but which is broken down to simpler, often more readily absorbable compounds, by the gut microflora (Forester et al., 2009). Bacterial metabolism of polyphenols includes ring- fission, and leads to a complex range of metabolites including aldehydes and phenolic acids. Many of these compounds are taken up into the circulation by passive absorption across the colon, and may also exert local anti-inflammatory activity in the gut lumen, which could be important for the maintenance of mucosal homeostasis and health (Larrosa et al., 2009).

14. CAROTENOIDS Carotenoids are terpenoids containing forty carbon atoms, and are found throughout the plant kingdom, mainly as components of chloroplasts, where they occur as pigments in close association with the photosynthetic apparatus. The two main classes of carotenoids are the carotenes, which contain no oxygen atoms, and the xanthophylls, which do. There are about 600 known carotenoids in nature, but relatively few are thought to be of nutritional significance for humans.

15. CAROTENOIDS-2 The provitamin A carotenoids (beta-carotene, alpha-carotene, gamma-carotene and beta-cryptoxanthin) are important because they are converted in the human intestinal mucosa to vitamin A. Beta-carotene and other carotenoids are potent antioxidants, and certain compounds, including the xanthophyll lutein, accumulate in the macula lutea of the human eye and the corpus luteum of the ovaries, where they are thought to plan an important protective role against free-radical mediated damage. Because of their well-established nutritional role in vitamin A metabolism, and their putative function as phytochemicals in their own right, the bioavailability of carotenoids has received much attention.

16. CAROTENOIDS-3 Being both hydrophobic and tightly bound within robust intracellular structures, the bioavailability of carotenoids depends upon their physical release from the plant tissue, and incorporation into a suitable lipid phase, either during food processing or in the intestinal lumen during digestion. Having been released into the gut lumen as an emulsion, the absorption of carotenoids occurs via the mixed micelle phase formed in the presence of bile salts during lipid absorption. The presence of adequate quantities of lipid in the digesta is thus an essential prerequisite for uptake of carotenoids, and their bioavailability depends on the contemporaneous intake of dietary fat.

17. GLUCOSINOLATES The glucosinolates are another complex group of biologically active compounds, which occur in cruciferous plants, and enter the human food chain in Brassica vegetables such as cabbages, broccoli and brussel sprouts, and in cruciferous salad vegetables including mustard greens, rocket and radishes ( Mithen et al., 2000). They are stable, water-soluble glycosides, sequestered within the plant tissue until acted upon by endogenous hydrolytic enzyme, myrosinase , which is released by mechanical disruption of the tissue.

18. GLUCOSINOLATES-2 They are released from raw plant tissue during food preparation, or by chewing and digestion, and they are absorbed passively across the intestinal surface. Like flavonoids, they are rapidly metabolized both in the gut epithelial cells and in the liver. Petri et al. (2003) used intraluminal tubes to infuse liquidized broccoli containing the isothiocyanate sulforaphane into the intact human intestine, and to recover the luminal contents for analysis. Interestingly, the concentration of sulforaphane metabolites in the urine of human volunteers after consumption of a test-meal of broccoli depends on their genetic status in relation to one of the major classes of Phase II enzymes, glutathione-S transferase (GST), which varies markedly in activity between individuals because of polymorphisms in the genes coding for the various components of its super-family.

19. LECTINS The lectins, unlike the other main classes of phytochemicals reviewed here, are proteins, of diverse structure and high molecular weight. They occur in the human food chain mainly as plant constituents, but they are found in the animal kingdom as well. Their defining characteristic is their capacity to bind specifically to carbohydrates, and most notably to the carbohydrate moieties of glycoproteins or glycolipids that occur as constituents of cell membranes. It is this property that accounts for their frequent role in mechanisms involving specific bio-recognition phenomena, and for their laboratory use in cellular agglutination reactions.

20. LECTINS-2 Lectins are generally very resistant to digestion in the gut, and their high molecular weight makes them poor candidates for intestinal absorption. They do however frequently show a strong tendency to interact with glycoconjugation sites on the mucosal surfaces of the intestine, and this is thought to account for many of their well documented biological activities in the gastrointestinal tract. Linderoth et al. (2006) showed that the effects on the gut mucosa occurred when the lectin was given by direct introduction into the alimentary tract (enteral exposure), but not when it was given by sub-cutaneous injection. However subcutaneous exposure did lead to effects on systemic organs not seen after enteral exposure. These results suggest that this lectin is highly biologically active within the gut lumen but is unlikely to be absorbed and become available to other organs via the circulation.

21. PHYTOCHEMICALS AND THEIR HEALTH-PROMOTING EFFECTS Phytochemicals exerts certain health benefits. Below are some health benefits; Phytochemicals as antioxidants Blocking and suppressing the growth of tumours . Modifying cardiovascular physiology

22. PHYTOCHEMICALS AS ANTIOXIDANTS Free radicals are highly reactive, short-lived species generated by a variety of biological mechanisms, including inflammation or as a side effect of the reactions occurring during normal oxidative metabolism. The fact that polyphenols and other secondary plant metabolites exhibit strong antioxidant activity in vitro led to the hypothesis that many of the putative protective effects of fruits and vegetables against cardiovascular disease and cancer are a direct consequence of strengthened antioxidant defences . Other studies have confirmed that dietary intervention with flavonoid-rich berries and other fruits leads to a significant increase in the antioxidant activity in human plasma (Pedersen et al., 2000), but the causal relationship between this effect and reductions in the risk of disease remains largely hypothetical.

23. BLOCKING AND SUPPRESSING THE GROWTH OF TUMOURS The development of cancer is a prolonged, multi-stage process, involving a progressive series of molecular events, beginning with damage to DNA in a single dividing cell. Cells that have undergone the first step of initiation and continue to divide and multiply, are increasingly vulnerable to further mutations, leading to an increasingly abnormal phenotype that gradually acquires the ability to migrate to other tissues and establish secondary tumours . Some of the earliest studies on the ability of natural food-borne chemicals to inhibit the development of cancer were conducted by Wattenberg, who observed that anticarcinogenic chemicals could be defined as either blocking agents, which act immediately before or during the initiation of carcinogenesis by chemical carcinogens, or as suppressing agents, which act at later stages of promotion and progression.

24. MODIFYING CARDIOVASCULAR PHYSIOLOGY Like cancer, cardiovascular disease, which includes both coronary heart disease and stroke, is a major cause of both death and long-term morbidity in the developed world, and a similar amount of effort has been devoted toward understanding its causes at the cellular and molecular level. All the major and minor blood vessels, including the capillaries, are lined by squamous epithelial cells, which collectively comprise the endothelium. Endothelial cells play a crucial role in the maintenance of normal vascular physiology through their surface properties, their barrier functions and their importance in the regulation of vasodilation.

25. MODIFYING CARDIOVASCULAR PHYSIOLOGY-2 Cocoa powder, which is prepared from pods of the cocoa tree Theobroma cacao, is amongst the most promising sources of biologically active flavonoids, principally oligomeric procyanidins, currently available to the food industry. The cocoa supplementation induced significant vasodilation, which was reversed by infusion of a nitric oxide synthase inhibitor. In another controlled trial with chocolate, it was shown that consumption of moderate daily quantities (46 g) of dark chocolate, rich in flavonoids, led to a reduction in blood pressure.

26. CONCLUSION Whilst it is probably true to say that the evidence for protective effects of diets rich in fruits and vegetables against chronic disease has tended to become less impressive with the passage of time, our understanding of the biological effects of their constituent phytochemical has grown at a near exponential rate. Clearly the so-called antioxidant hypothesis for the protective effects of fruits and vegetables remains, at best, unproven. There is little doubt that plant foods are rich in antioxidant constituents, but their poor bioavailability probably limits their effectiveness as regulators of antioxidant damage in humans. Nevertheless, the last two decades have provided an abundance of new evidence for other potentially important protective mechanisms operating at the cellular and organ levels, and research on all aspects of phytochemicals and their physiological and biochemical effects continues apace.

27. REFERENCES Chan, A.T., Giovannucci, E.L., Meyerhardt , J.A., Schernhammer , E.S., Curhan , G.C., et al. (2005) Long term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. Journal of the American Medical Association, 294, 914–923. Chou, F.P., Chu, Y.C., Hsu, J.D., Chiang, H.C. and Wang, C.J. (2000) Specific induction of glutathione S-transferase GSTM2 subunit expression by epigallocatechin gallate in rat liver. Biochemical Pharmacology, 60, 643–650. Chow, H.H., Salazar, D. and Hakim, I.A. (2002) Pharmacokinetics of perillic acid in humans after a single dose administration of a citrus preparation rich in d-limonene content. Cancer Epidemiology, Biomarkers and Prevention, 11, 1472–1476.

28. REFERENCES-2 Davison, K., Berry, N.M., Misan , G., Coates, A.M., Buckley, J.D., et al. (2010) Dose-related effects of flavanol-rich cocoa on blood pressure. Journal of Human Hypertension, 24, 568–576. Day, A.J., Gee, J.M., DuPont, M.S., Johnson, I.T. and Williamson, G. (2003) Absorption of quercetin-3 glucoside and quercetin-4’-glucoside in the rat small intestine: the role of lactase phlorizin hydrolase and the sodium-dependent glucose transporter. Biochemical Pharmacology, 65, 1199–1206. Djousse , L., Hopkins, P.N., North, K.E., Pankow, J.S., Arnett, D.K., et al. (2010) Chocolate consumption is inversely associated with prevalent coronary heart disease: The National Heart, Lung, and Blood Institute Family Heart Study. Clinical Nutrition, 30(2), 182–187