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The CFI discussed above consist of a complex mixture of phytochemicals, and for most, only partial analysis has been performed. However, often (one of ) the active ingredients have been identified for some of the extracts. These ac-tive ingredients are often flavonoids and hydroxycinnamates, but also terpenes, other phenolics, steroids, etc. Most flavonoids and hydroxycinnam-ates are found in the plant and in extracts from the plant attached to a sugar or organic acid, and consequently have a very low biological activity. For

significant biological activity, the sugar or organic acid must be cleaved by glycosidases, esterases, or other hydrolytic enzymes, into the aglycone form.

The site of this hydrolysis is either the small intestine (enterocyte-derived enzymes or secreted enzymes) or the colonic microflora. Fermentation of the extract also produces the same effect.

Most of the biological activities of individual compounds are associated with inhibition of carcinogenesis, since a large number of in vitro tests for anticarcinogenicity have been reported. Few assays in vitro can be used to screen for other effects on the gut, and very few clinical studies have been car-ried out. The activities of some examples are discussed below.

A. Acacetin

Acacetin is a flavonoid that occurs in plants as a glycoside with attached glucose, rhamnose, or glucuronic acid moieties. In the aglycone form, it is an antioxidant in vitro although this is a common property of most flavonoids. It induces UGT defense mechanisms in cells in vitro (90), inhibits cytochrome P450s CYP1A and CYP1B1 (91), induces terminal differentiation of HL-60 cells (92), inhibits topoisomerase l–catalyzed DNA ligation (93), and inhibits B(a)P-induced mutagenesis in hamster embryo-cell-mediated V79 cell muta-tion assay (94). All of these activities are associated with a decreased risk of carcinogenesis, incuding colon carcinogenesis.

B. Agastinol, Agastenol

These are recently reported novel lignans that inhibit etoposide-induced apoptosis of U937 cells (95). Very few data are available on effects on the gas-trointestinal tract.

C. Anethole

Anethole has a broad range of biological activities related to possible action on the gastrointestinal tract. It exhibits local anesthetic activity in vivo in rats (96), is antimicrobial (97), and may possibly have antispasmodic, digestive, and secretolytic activities, although the mechanisms of these activities are not reported. At relatively high doses, anethole shows dose-related antigenotoxic effect against procarbazine and urethane in mice (98), and inhibits TNF-induced cellular responses such as NF-kB activation, TNF-TNF-induced lipid peroxidation, and reactive oxygen species, and suppresses TNF-activation of AP-1, c.jun N-terminal kinase, and MAPK-kinase (99). Possible anticarcino-genic action is suggested since rats fed anethole show induction of hepatic phase II but not phase I enzymes in the liver (100).

D. hhhhhhhhhhhhh-Caryophyllene

h-Caryophyllene shows some antibacterial activity (101), and has cytopro-tective and anti-inflammataory effects in the stomach against necrotizing agents such as ethanol and acetic acid, but does not affect secretion of gastric acid and pepsin (102). Some anticarcinogenic activity is suggested since it is toxic to tumor cell lines (103), and induces small-intestinal glutathione transferase (49).

E. Chlorogenic Acid, Caffeic Acid

Chlorogenic acid is caffeic acid linked to quinic acid. Chlorogenic acid exhi-bits some relatively weak anticarcinogenic effects and reduces the incidence of aberrant crypt foci in rats (104). However, derivatives such as rosmarinic acid (see below) and caffeic acid phenethyl ester (from honey bee hive propiolis) have greatly enhanced biological activities.

F. Chrysophanol

Chrysophanol is antifungal (105), inhibits cytochrome P450 (106), and has po-tential antiallergic activity via inhibition of hyalonuridase and histamine re-lease from mast cells (107).

G. Cinnamaldehyde, 2V-Hydroxycinnamaldehyde

Cinnamaldehyde has antimicrobial activity against some pathogens (108), in-hibits rat jejunal Na⁺-K⁺-ATPase (53), inhibits lymphoproliferation, and induces a T-cell differentiation through the blockade of early steps in signaling pathway leading to cell growth (109).

H. Emodin

Emodin is anti-inflammatory against carageenan-induced edema in rats (110) and emodin and its metabolites have a long half-life in the plasma of rats (f50 hr) (111). Emodin exhibits a range of anticarcinogenic activities in vitro, including inhibition of formation of DNA adducts induced by 1-nitropyrene (112), modulation of cellular transformation and proliferation (113), inhibi-tion of NF-kB activainhibi-tion and expression of adhesion molecules (114), inhibition of casein kinase II (114a), and induction of apoptosis (115), but emodin induces cytochromes P450 1A1 and 1B1 in human lung cell lines (116). Emodin also induced muscle contractions due to Ca²⁺release in skel-etal muscle, as a result of influx of extracellular Ca²⁺ through voltage-dependent Ca²⁺channels of the plasma membrane (117).

I. Glycyrrhizic Acid, Glycyrrhizin

The triterpenoid glycyrrhizin is anti-inflammatory and is metabolised to the aglycone glycyrrhizic acid, which inhibits 11-h-hydroxysteroid dehydroge-nase, involved in corticosteroid metabolism. The aglycone inhibited N-acetyltransferase activity in human colon tumor cell lines, and inhibited the formation of DNA adducts (118). Although glycyrrhizin did not directly induce apoptosis, it enhanced Fas-mediated apoptotic body formation and DNA fragmentation in T-cell lines (119). The action of licorice root, the main source of glycyrrhizin, on cancer has been reviewed (71).

J. Hesperidin, Hesperetin

Hesperetin is a flavonoid that exhibits a number of biological activities; hes-peridin is the glycosylated form. Mandarin juice rich in heshes-peridin and h-cryptoxanthin reduced azoxymethane-induced colon carcinogenesis in rats (120); hesperidin reduced phorbol-ester induced inflammation in mouse skin (121); hesperidin was anti-inflammatory against rat colitis induced by trini-trobenzenesulfonic acid and protected against urinary bladder carcinogenesis in mice (122); and hesperidin protected against rat esophageal carcinogenesis (123). Hesperidin methylchalcone is a drug used against chronic venous insufficiency since it reduces activation of phospholipase and ameliorates the decrease in ATP in hypoxia-treated endothelial cells (124).

K. Linalool

Linalool is a monoterpene and an anticonvulsive agent (125), and is also hypnotic and hypothermic (126), via inhibition of acetylcholine release in the mouse neuromuscular junction. It is a sedative in humans (127).

L. Nobiletin

Nobiletin is a flavonoid that occurs exclusively in citrus fruits. It is antimeta-static in mice and inhibited peritoneal dissemination of gastric cancer, at least partly through inhibition of metalloproteinases (128). Nobiletin protected against the appearance of gastric hemorrhagic lesions induced by ethanol but not aspirin in the guinea pig, and alone had no effect on the potential difference. Nobiletin also relaxed the contractions induced by acetylcholine, electrical stimulation, and histamine in isolated guinea pig ileum. The anti-ulcer effects of nobiletin were ascribed to maintenance of the mucosal barrier and inhibition of gastric motor activity (129). It also suppressed azoxy-methane-induced colonic aberrant crypt foci in rats (130).

M. Proanthocyanidins

Procyanidins or proanthocyanidins are oligomeric flavan-3-ol flavonoids, which occur in high amounts in some Western diets owing to their presence in cocoa/chocolate, red wine, and also in some supplements such as grape seed extract. Because they are oligomers, a number of different compounds are found naturally, consisting of either eipcatechin or catechin monomers linked in different ways with a degree of polymerization of 2–6 and more. Analytical limitations make it difficult to obtain pure oligomers above 6. Although procyanidins are only poorly bioavailable, they exert a number of effects in vivo although not specifically on the gut.

N. Rhein

Rhein is a highly biologically active anthraquinone that is a component of senna. It has a number of effects on the gastrointestinal tract, including in-duction of ion secretion, chemotaxis, and apoptosis in the intestinal Caco2 cell line via nitric oxide generation (131), inhibits the growth of Helicobacter pylori(132), modifies the peristaltic reflex of the inverted guinea pig ileum (133), inhibits glucose uptake (134), and decreases transit time in rats with a prostaglandin-dependent mechanism (135). Some anticarcinogenic activity has also been claimed, since rhein modulates topoisomerase II, and inter-calates DNA (136).

O. Rosmarinic Acid

Rosmarinic acid is one of the most effective antioxidants, and it induced phase II detoxifying enzymes in rat liver but not cytochrome P450 (phase I) enzymes (137). It also inhibited cell proliferation (138), reduced lipopolysaccharide-induced liver injury in mice (138a), and may have some undefined antide-pressive effects (139).

P. Tangeretin

Tangeretin is a flavonoid that affects cell-cell adhesion and downregulates the IL-2 receptor on T lymphocytes and natural killer cells (140), and may cross the blood-brain barrier in rats (141), although no specific effects on the gut have been reported.