Anti-Ulcer Potential of Flavonoids N. S. Parmar' And

Indian J Physiol Phllrmllcol 1998; 42 (3) : 343-351

REVIEW ARTICLE

ANTI-ULCER POTENTIAL OF FLAVONOIDS

N. S. PARMAR' AND SHIKHA PARMAR"

K. B. Institute of Pharmaceutical "''''Department of Pharmacology, Educatiort & Research, and L. M. College of Pharmacy, Gandhinagar - 382 023 Ahmedabad - 380009

(Received on October 10, 1997)

The flavonoids are a group of low environmentally related dietary conditioned molecular weight, naturally occurring, plant resistance to disease (2). This concept is products widely distributed in the based on the evidence that flavonoids and vegetarian kingdom and all are based on related compounds synthesized in plants the parent compound flavone (2 with antiviral, antifungal, bacteriostatic and phenylchromone or 2-phenylbenzopyrone). immunostimulant actions may be absorbed They occur in fruits, vegetables, nuts, seeds into the body and attached irreversibly to leaves, flowers and barks. The average daily blood cells. In the body, in addition to any western diet contains about 1 g of mixed potential action against pathogens, certain flavonoids, an amount that might be of these compounds potentiate enzymes sufficient to achieve pharmacologically which detoxify carcinogenic hydrocarbons, significant concentration in tissues (1). exhibit anti-inflammatory activity, exert anti-adhesive action on blood cells and show A biological function of this group of antithrombogenic activity (1). A current compounds in man and animals was first account on the importance of dietary suggested in the year 1936 by Szcnt cosntituents in the prevention of coronary Gyorgyi who reported that crude heart disease also highlights the protective preparations of vitamin C obtained from effects of flavonoids through their anti natural sources, were more effective than oxidant property (3). the pure vitamin in alleviating the capillary lesions and prolonging the life of scorbutic Pathogenesis of peptic ulcer disease : animals. The unknown substance that Peptic ulcers are thought to develop protected the capillaries was isolated from because of an imbalance between aggressive lemon and was called citrin. Later on, a factors (acid, pepsin, bile salts) and variety of naturally occurring substances defensive factors (mucus, bicarbonate, blood were found to possess such action and they flow, eptithelial cell restoration, were eventually identified as flavonoids. prostaglandins).

Recently, it has been postulated that Most duodenal ulcers occur in the first human body has a capacity for an part of the duodenum. Pathophysiological -Corresponding Author 344 Parmar and Parmar Indian J Phyaiol Pharmacol 1998; 42{3) abnormalities producing duodenal ulcers are Inspite of the advancements in studies complex, but are thought to be related to on the pathophysiology of peptic ulcer an absolute or relative increase in duodenal disease leading to the elucidation of various acidity. Several theories have been proposed mediators implicated in its genesis and to explain the complex inter-relationship introduction of highly effective histamine between acid secretion and duodenal ulcer. H 2 antagonists and gastric proton pump For example a person with duodenal ulcer inhibitors, we have yet to discover an may have an abnormally high vagal tone; effective anti-ulcer drug which not only excessive humoral (gastrin) stimulation of heals the peptic ulcers but also prevents acid; impaired inhibition of gastric acid their recurrence. This review gives an secretion or a greater capacity to secrete account of various flavonoids so far studied acid. Recently, Helicobacter pylori which is for their anti·ulcer activity. known to colonize the antral region of gastric mucosa, has also been implicated in The unti-ulcer potential of fl.auonoids the pathogenesis of peptic ulcer disease. Early reports: Capillary integrity being vital to normal functioning of mucous Most benign gastric ulcers are located membranes, experimental and clinical in the antrum of the stomach on the lesser lesions of the gastric mucosa have been curvature, just distal to the acid secreting employed by some investigators to study the mucosa. Although the pathophysiology of pharmacological activity of flavonoids. Vogin gastric ulcer has still not been fully and Rossi (4) reported that a combination elucidated, most studies suggest defect in of orange bioflavonoid complex with vitamin antral-pylorus-duodenal motility. Abnormal C protected against the ulcers induced by motility patterns permit duodenal contents histamine in guineapigs and by reserpine to reflux into the stomach with resultant in rats. Similarly, vitamin C when combined damage to gastric mucosa. Delayed gastric with rutin could protect against the gastric emptying can increase exposure of acid, ulceration induced by phenylbutazone in pepsin and refluxed duodenal contents to rabbits (5). Ciaceri and Attaguilc (6) the gastric mucosa. It appears that the bile reported the protective effect of luteolin and salts and pancreatic secretions damage the apigenin against histamine induced ulcers gastric mucosa and allow back-diffusion of in guinea pigs and in pylorus ligated rats. hydrogen ions. This action is thought to result in ulcer formation. The gastric Parmar (7) conducted a systematic study mucosal barrier may also be damaged by on the anti-ulcer activity of various chemical drugs such as aspirin and NSAIDs whose groups of flavonoids like flavones, flavonols, mechanism is related to inhibition of flavans, flavanones and chalcones under an cyclo-oxygenases responsible for synthesis of cytoprotective prostaglandins. Thus ICMR sponsored research project. His study evidence supports the importance of primary revealed the anti-ulcer potential of defects in gastric mucosal resistance andlor compounds like p-hydroxyethylrutosides, direct gastric mucosal injury as the most gossypin, naringio, naringenin and (+) important elements in the pathogenesis of cyanidanol-3 i.e., (+}-catechin. They gastric ulcers. significantly reduced the severity of Indian J Physiol Pharmacol 1998; 42(3) Anti-Ulcer Potential of Flavonoids 345

ulceration induced by pylorus ligation, established a close link between gastric restraint, reserpine, aspirin, phenylbutazone ulceration and reduction of gastric mucosal and indomethacin in rats and by histamine histamine levels in man. in guinea pigs. These compounds also exhibited marked antisecretory activity in These studies further substantiated the pylorus ligated rats. work of Ritchie et al (3) who had shown that the level of endogenous tissue Histidine decarboxylase Ln ulceration: histamine could be markedly decreased in Almost simultaneously with these rats maintained on a pyridoxine deficient studies, Reimann et al (8) reported the diet for two weeks and these reduced levels gastric anti-ulcer activity of (+)-cyanidanol provided significant protection against the 3 in rats immobiliz.ed for eight hours. Based development of restraint induced ulceration on the study of Levine and Senay (9) who in the glandular portion of the rat stomach had shown that brocresine a histidine and significantly reduced the volume of decarboxylase inhibitor afforded protection gastric secretion and free and total acid from the ulcerogenic effects of stress and production in pylorus ligated rats. that of Lorenz. et al (10) on the histidine Pyridoxine in all probability acts as a decarboxylase inhibitory activity of (+) catalyst for histidine decarboxylase, the cyanidanol-3, we studied the anti-ulcer enzyme responsible for the endogenous potential of(+)- cyanidanol-3, using various formation of histamine. models of gastric ulceratation in rats and guinea pigs (ll). In a preliminary clinical 3-Methoxy-5, 7, 3', 4'-tetrahydroxy flalJan investigation Wendt ct al (12) studied the (Meciadanol) : efficacy of (+)-cyanidanol·3 in reducing the gastric tissue histamine content in patients As the studies on <+)-cyanidanol-3 were with gastric and duodenal ulcers and acute under progress, the Chemical Laboratories gastritis. After oral administration of (+) of Zyma SA Nyon, Switzerland developed a cyanidanol-3 (5 x 1000 mg daily for 8 days) congener of (+)-cyanidanol·3, meciadanol the biopsies were taken daily from the which underwent detailed pharmacological normal human volunteers and the patients and clinical investigations. It appeared as mentioned above. Similar reduction in to be comparatively more promising histamine could be observed in patients with compound as far as the pharmacological, stomach ulcer disease and gastritis after pharmacokinetic and preliminary clinical treatment with <+)-cyanidanol-3. They also studies were concerned (14). It has been showed that the histamine content of gastric shown by Hackett and Griffiths (15) that mucosa significantly increased in patients meciadanol, unlike (+)-cyanidanol-3 does with urticaria and food allergy after the not undergo micronoral ring fission in the local application of the antigen to gastric intestine, which has been considered to be mucosa. This increase in gastric histamine the major pathway of flavonoid metabolism levels could be significantly decreased by (16). This difference may partly account the prior administration of (+)-cyanidanol for the increased bioavailability and 3. These studies for the first time more pronounced anti-ulcer activity of 346 Parmar and Parmar Indian J Physiol Pharmacol 1998; 42{3J

this compound as compared to (+) subacute and chronic toxicity studies in cyanidanol-3. rats, administration by intravenous dose in dogs and the local tolerance studies in Parmar and Ghosh (17) and Parmar and rabbits showed that the compound was safe Hennings (18, 19) reported the gastric anti for conducting the clinical investigations by ulcer activity of meciadanol using various oral route in human beings. It has been models of experimentally induced ulcers, found to be devoid of any teratogenic viz, the pylorus ligated rats, restraint ulcers potential in rats and rabbits. It did not and gastric mucosal damage induced by produce any mutagenic effect in the Ames aspirin, phenylbutazone, indomethacin, test and in the cytogenic test done on bone ibuprofen and reserpine in rats. It possessed marrow cells of mouse. It was also found significant anti-ulcer activity in these inactive in the carcinogenicity test on BALP models and appeared slightly more potent 3T3 mouse cells in culture (14). and better bioavailable as compared to (+) cyanidanol-3. Pharmacokinetic studies on meciadanol show that the orally administered drug is The antisecretory activity of meciadanol well absorbed and gradually excreted in was further studied in conscious gastric urine and faeces during a period of 72 hours fistula cats using pentagastrin, insulin and in rats, mice and marmosets. It is food as secretory stimulants whereas metabolized by methylation of the pentagastrin stimulated gastric secretion hyroxyphenol groups of the B nucleus in was inhibited only by a high Lv. dose of 3,3' dimethoxy 5,7, 4'-trihydorxy flavan. 200 mg/kg of meciadanol, food and insulin This metabolite is then conjugated and induced gastric secretion was inhibited with excreted in the urine and bile (15). a dose of 25 mg/kg given intravenously (20). It was found to possess similar antisecretory No breakdown products of meciadanol or activity in rats subjected to pylorus ligation its principal metabolite by the intestinal for 6 hours and it was as effective as the tract microflora due to ring fission have

H 2 - antagonist cimetidine in these been observed in any of the species tested experiments (20. Further studies showed because the substitution in position 3 that meciadanol promotes the healing of probably stabilises the molecule. There was gastric ulcers induced by restraint in also no evidence of the demethylation of the rats (22). The healing took place compound at any stage of the metabolism. significantly faster in the rats receiving The fact that it is not demethylated in lJilJO meciadanol than in control rats. It also means that its action is not due to its produced a significant synergist.ic act.ion conversion to (+)-cyanidanol-3 in the body. when used in combination with cimelidine This stability of ether link in position 3 is in different. models of experimental also likely to persist in man OS, 16). ulceration in rats. The results of preliminary clinical trials Meciadanol had undergon!! d!!tailed showed a significant potential for developing preclinical toxicity studies. The acute, it into a promising anti-ulcer drug. It Indian J Physiol Pharmacol 1998; 42(3) Anti-Ulcer Potential of Flavonoids 347

showed protective effect against aspirin However, these studies point towards a induced irritation of the human gastric strong possibility of finding out a safe and mucosa as demonstrated by measuring the effective flavonoid possessing histidine gastric potential difference (23) according decarboxylase inhibitory and anti·ulcer to the method of Laule et al (24). Oral activity in future (22). Recent publications pretreatment with 250-1000 mg of of Murakami et al (27) and Alarcon de la meciadanol reduced the degree of irritation Lastra et al (28) reveal the property of of gastric mucosa in a dose dependent gastric H-+, K-+-A1'Pase inhibition in manner. In volunteers treated with catechins and that of lipoxygenase inhibition meciadanol, the histamine content was in silymarin respectively. These findings significantly reduced in the fundus, corpus also support the above contention and and antrum of the stomach (12). In another provide impetus for further indepth studies study on the effect of meciadanol on gastric on anti-ulcer profiles of navonoids. Another secretion and aspirin induced gastric recent publication reveals the dose mucosal injury in humans, Konturek et al dependent reduction in gastric mucosal (25) found that meciadanol did not affect damage and the mucosal content of platelet either basal or pentagastrin stimulated activating factor by flavonols like rutin, gastric acid secretion or pepsin secretion quercetin and kaempferol (29). and did not produce any endoscopic or histological changes in the stomach or Sofalcone duodenum. Nevertheless, it prevented aspirin-induced microbleeding and aspirin In Chinese medicine, a crude drug called induced DNA loss suggesting that gastric Kohzukon (Sophora slIbprostrata Chun ot mucosal histamine is involved in the 1'. Chen) has been used in the treatment of mucosal injury caused by aspIrin. digestive diseases. It has been reported that Subsequently, Konturek et al (26) have sophoradin, a compound isolated from the established a true cytoprotective effect of root of this ancient Chinese plant exhibits meciadanol on ethanol and aspirin induced anti-ulcer activity in experimental models. gastric mucosal damage in rats which was One of the sophoradin derivatives, an comparable to that of 16, 16-dimethyl PGE • 2 isoprenyl l1avonoid known as soralcOlw (2' It was neither mediated by the reduction of ca rboxy-methoxy-4-4'-bis (3-methyl-2 gastric or pepsin a<;,tivity nor by enhancing butenyloxy) - chalcone has been extensively the endogenous muscosal PG1 2 levels. studied for its anti-ulcer potential. Sofalcone prevents acute gastric ulceration induced by Inspite of its highly effective anti-ulcer acidified aspirin, water immersion and profile and unique mode of action, this restraint ulcers (30) and has a cytoprotective compound could not be inll'oduced in effect against 0.6 N HCI and aboslute therapeutics as an useful anit-ulcer drug. As ethanol induced mucosal lesions in rat catechins were shown to produce hemolytic stomach (30, 31, 32) and taurocholate anemias, further attempts to develop induced gastritis in rats (33). Prostaglandins meciadanol and other potential compounds have been shown to be involved in its anti as anti-ulcer drugs were given up. ulcer and cytoprotective effects (30). It 348 Parmar and Parmar Indian J Physio! Pharmacol 1998; 42(3)

TABLE 1 : Naturally occurring and semisynthetic flavonoids with significant anti·ulcer activity.

Planls E((ectiue compounds Models studied References

Sophora Subprostata Sophoradin Experimental gestric 39 ulcers in rata and guinea pigs. Pylorus ligated rats Sofalcone Now in dinical use 37 (Semisynthetic) Glycyrrhiza glabra Hydroxychalcones HCI-ethanol, water 38 immersion and acetic acid induced gastric ulcers in rats Silybim marianum Silymarin Ethanol, cold-restraint, 2B pylorus ligration in rats Rhamnus procubens Kaempferol Pylorus ligation and 40 restraint in rats. histamine in guineapigs Anacardium occidentale Catechins Pylorus ligation, NSAIDs in 11, 16, 17, Linn and other lIources rats. Histamine in guinea pigs 20,21,22, 23, 24, 25, 26 (+l-Cyandidanol-3 Gastric H', K+ ATPase 27 Catechins inhibition Meciadanol Undergone clinical trials 24, 25 (Semisynthetic) Erica IIndevalensis Flavonoid Extract Cold stress. Pylorus ligation, 41 Ethanol in rata Amcntoflavone Pylorus ligation. 42, 43 restraint in rats: histamine in guineapigs Genista rumelica Genistine Experimental gastric ulcers 44 (Tolal flavonoid in rats mixture) Sideritis leucantha Hypolaetin-8-0 Ethanol and aspirin in rats 45 beta-D-glucoside Eucalyptus maculata Quercetin, Cold + restraint and 46,47 Hook; Citrus paradisi Naringenin pylorus ligation in rats Macfad Aurantii frustus Nobiletin and Ethanol and aspirin in rats 4B immaturus Marmin Diltrichia Viscosa Flavonoid Ethanol, HCI, Hypertonic 49 fraction saline and indomethacin in rats Cistus incanus Flavonoid HCI, ethanol indomethacin, 50 extract reserpine and serotonin in rats. Indian J Physiol Pharmacol 1998,42(3) Anti-Ulcer Potential of Flavonoids 349 inhibits the activity of PG metabolizing them, 2', 4' - dihydroxychalcone appears to enzyme lS·hydroxy·PG-dehydrogenase and be most promising compound for elevates the PGE2 content of the gastric further development as an anti-ulcer mucosa in rats subjected to absolute ethanol agent. induced gastric mucosal damage and taurocholate induced gastritis (30, 33). A number of publications have appeared during the last two decades describing the Sofaleone has been clinically tried In anti-ulcer potential of f1avonoids or Japan for the treatement of gastroduodenal f1avonoidal extracts from plants. Some ulcers by a number of workers (34-37). It important reports have been summarized in has been found particularly useful in Table I. accelerating the healing of gastric ulcers which were shown to be accompanied by a CONCLUSION deficiency of PG biosynthesis in gastric mucosa. During the recent years flavonoids have been the most widely studied natural lIydroxychnloncs compounds for their anti·ulcer potential. Both meciadanol and sofalcone have been Taking a lead from the studies of studied for their clinical effectiveness and sofalcone, Yamaoto et al (38) studied the were found effective in the clinical trials. gastroprotective effect of a number of Though these compounds could not be hydroxych}\lcones obtained from various developed and marketed as effective anti plants against necrotizing agents - induced ulcer agents, they have opened new vistas gastric ulcers in rats viz. I-lei-ethanol and in ulcer research and pharmacologists are NaOH and those induced by water still working to find out an effective and immersion stress and acetic acid. Amongst safe anti-ulcer drug from this class of the nine hydroxychalconcs tested by naturally occurring compounds.

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