ANTI-ULCER POTENTIAL OF FLAVONOIDS

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

REVIEW ARTICLE

ANTI-ULCER POTENTIAL OF FLAVONOIDS

N. S. PARMAR* AND SHIKHA PARMAR**

K. B. Institute of PharmaceuticalEducation & Research,Gandhinagar - 382 023

and**Department of Pharmacology,

L. M. College of Pharmacy,Ahmedabad - 380009

( Received on October 10, 1997)

The flavonoids are a group of lowmolecular weight, naturally occurring, plantproducts widely distributed in thevegetarian kingdom and all are based onthe parent compound flavone (2-phenylchromone or 2-phenylbenzopyrone).They occur in fruits, vegetables, nuts, seedsleaves, flowers and barks. The average dailywestern diet contains about 1 g of mixedflavonoids, an amount that might besufficient to achieve pharmacologicallysignificant concentration in tissues (1).

A biological function of this group ofcompounds in man and animals was firstsuggested in the year 1936 by Szent-Gyorgyi who reported that crudepreparations of vitamin C obtained fromnatural sources, were more effective thanthe pure vitamin in alleviating the capillarylesions and prolonging the life of scorbuticanimals. The unknown substance thatprotected the capillaries was isolated fromlemon and was called citrin. Later on, avariety of naturally occurring substanceswere found to possess such action and theywere eventually identified as flavonoids.

Recently, it has been postulated thathuman body has a capacity for an

environmentally related dietary conditionedresistance to disease (2). This concept isbased on the evidence that flavonoids andrelated compounds synthesized in plantswith antiviral, antifungal, bacteriostatic andimmunostimulant actions may be absorbedinto the body and attached irreversibly toblood cells. In the body, in addition to anypotential action against pathogens, certainof these compounds potentiate enzymeswhich detoxify carcinogenic hydrocarbons,exhibit ant.i-dnfl amrn ato ry activity, exertanti-adhesive action on blood cells and showanti thrombogenic activity 0). A currentaccount on the importance of dietarycosntituents in the prevention of coronaryheart disease also highlights the protectiveeffects of flavonoids through their anti-oxidant property (3).

Pathogenesis of peptic ulcer disease "

Peptic ulcers are thought to developbecause of an imbalance between aggressivefactors (acid, pepsin, bile salts) anddefensive factors (mucus, bicarbonate, bloodflow, eptithelial cell restoration,prostaglandins) .

Most duodenal ulcers occur in the firstpart of the duodenum. Pathophysiological

*Corresponding Author

344 Parmar and Parmar

abnormalities producing duodenal ulcers arecomplex, but are thought to be related toan absolute or relative increase in duodenalacidity. Several theories have been proposedto explain the complex inter-relationshipbetween acid secretion and duodenal ulcer.For example a person with duodenal ulcermay have an abnormally high vagal tone;excessive humoral (gastrin) stimulation ofacid; impaired inhibition of gastric acidsecretion or a greater capacity to secreteacid. Recently, Helicobacter pylori which isknown to colonize the antral region ofgastric mucosa, has also been implicated inthe pathogenesis of peptic ulcer disease.

Most benign gastric ulcers are locatedin the antrum of the stomach on the lessercurvature, just distal to the acid secretingmucosa. Although the pathophysiology ofgastric ulcer has still not been fullyelucidated, most studies suggest defect inantral-pylorus-duodenal motility. Abnormalmotility patterns permit duodenal contentsto reflux into the stomach with resultantdamage to gastric mucosa. Delayed gastricemptying can increase exposure of acid,pepsin and refluxed duodenal contents tothe gastric mucosa. It appears that the bilesalts and pancreatic secretions damage thegastric mucosa and allow back-diffusion ofhydrogen ions. This action is thought toresult in ulcer formation. The gastricmucosal barrier may also be damaged bydrugs such as aspirin and NSAIDs whosemechanism is related to inhibition ofcyclo-oxygenases responsible for synthesisof cytoprotective prostaglandins. Thusevidence supports the importance of primarydefects in gastric mucosal resistance and/ordirect gastric mucosal injury as the mostimportant elements in the pathogenesis ofgastric ulcers.

Indian J Physiol Pharmacol 1998; 42(3)

Inspite of the advancements in studieson the pathophysiology of peptic ulcerdisease leading to the elucidation of variousmediators implicated in its genesis andintroduction of highly effective histamineH2 antagonists and gastric proton pumpinhibitors, we have yet to discover aneffective anti-ulcer drug which not onlyheals the peptic ulcers but also preventstheir recurrence. This review gives anaccount of various flavonoids so far studiedfor their anti-ulcer activity.

The anti-ulcer potential of flavonoidsEarly reports : Capillary integrity beingvital to normal functioning of mucousmembranes, experimental and clinicallesions of the gastric mucosa have beenemployed by some investigators to study thepharmacological activity of flavonoids. Yoginand Rossi (4) reported that a combinationof orange bioflavonoid complex with vitaminC protected against the ulcers induced byhistamine in guineapigs and by reserpinein rats. Similarly, vitamin C when combinedwith rutin could protect against the gastriculceration induced by phenylbutazone inrabbits (5). Ciaceri and Attaguile (6)reported the protective effect of lute olin andapigenin against histamine induced ulcersin guinea pigs and in pylorus ligated rats.

Parmar (7) conducted a systematic studyon the anti-ulcer activity of various chemicalgroups of flavonoids like flavones, flavonols,flavans, flavanones and chalcones under anICMR sponsored research project. His studyrevealed the anti-ulcer potential ofcompounds like ~-hydroxyethylrutosides,gossypin, naringin, naringenin and (+)-cyanidanol-3 i.e., (+)-catechin. Theysignificantly reduced the severity of


ulceration induced by pylorus ligation,restraint, reserpine, aspirin, phenylbutazoneand indomethacin in rats and by histaminein guineapigs. These compounds alsoexhibited marked antisecretory activity inpylorus ligated rats.

Histidine decarboxylase in ulceration :Almost simultaneously with these

studies, Reimann et al (8) reported thegastric anti-ulcer activity of (+ )-cyanidanol-3 in rats immobilized for eight hours. Basedon the study of Levine and Senay (9) whohad shown that brocresine a histidinedecarboxylase inhibitor afforded protectionfrom the ulcerogenic effects of stress andthat of Lorenz et al (10) on the histidinedecarboxylase inhibitory activity of (+)-cyanidanol-3, we studied the anti-ulcerpotential of (+)- cyanidanol-3, using variousmodels of gastric ulceratation in rats andguinea pigs (Ll.). In a preliminary clinicalinvestigation Wendt et al (12) studied theefficacy of (+ )-cyanidanol-3 in reducing thegastric tissue histamine content in patientswith gastric and duodenal ulcers and acutegastritis. After oral administration of (+)-cyanidanol-3 (5 x 1000 mg daily for 8 days)the biopsies were taken daily from thenormal human volunteers and the patientsas mentioned above. Similar reduction inhistamine could be observed in patients withstomach ulcer disease and gastritis aftertreatment with (+ )-cyanidanol-3. They alsoshowed that the histamine content of gastricmucosa significantly increased in patientswith urticaria and food allergy after thelocal application of the antigen to gastricmucosa. This increase in gastric histaminelevels could be significantly decreased bythe prior administration of (+ )-cyanidanol-3. These studies for the first time

Anti-Ulcer Potential of Flavonoids 345

established a close link between gastriculceration and reduction of gastric mucosalhistamine levels in man.

These studies further substantiated thework of Ritchie et al (13) who had shownthat the level of endogenous tissuehistamine could be markedly decreased inrats maintained on a pyridoxine deficientdiet for two weeks and these reduced levelsprovided significant protection against thedevelopment of restraint induced ulcerationin the glandular portion of the rat stomachand significantly reduced the volume ofgastric secretion and free and total acidproduction in pylorus ligated rats.Pyridoxine in all probability acts as acatalyst for histidine decarboxylase, theenzyme responsible for the endogenousformation of histamine.

3-Methoxy-5, 7, 3', 4'-tetrahydroxy {lavan(Meciadanol) :

As the studies on (+ )-cyanidanol-3 wereunder progress, the Chemical Laboratoriesof Zyma SA Nyon, Switzerland developed acongener of (+ )-cyanidanol-3, meciadanolwhich underwent detailed pharmacologicaland clinical investigations. It appearedto be comparatively more promisingcompound as far as the pharmacological,pharmacokinetic and preliminary clinicalstudies were concerned (14). It has beenshown by Hackett and Griffiths (15) thatmeciadanol, unlike (+ )-cyanidanol-3 doesnot undergo microfloral ring fission in theintestine, which has been considered to bethe major pathway of flavonoid metabolism(16). This difference may partly accountfor the increased bioavailability andmore pronounced anti-ulcer activity of


this compound as compared to (+)-cyanidanol-3.

Parmar and Ghosh (17) and Parmar andHennings (18, 19) reported the gastric anti-ulcer activity of meciadanol using variousmodels of experimentally induced ulcers,viz, the pylorus ligated rats, restraint ulcersand gastric mucosal damage induced byaspirin, phenylbutazone, indomethacin,ibuprofen and reserpine in rats. It possessedsignificant anti-ulcer activity in thesemodels and appeared slightly more potentand better bioavailable as compared to (+)-cyanidanol-3.

The antisecretory activity of meciadanolwas further studied in conscious gastricfistula cats using pentagastrin, insulin andfood as secretory stirn ulan ts whereaspentagastrin stimulated gastric secretionwas inhibited only by a high i.v. dose of200 mg/kg of meciadanol, food and insulininduced gastric secretion was inhibited witha dose of 25 mg/kg given intravenously (20).It was found to possess similar antisecretoryactivity in rats subjected to pylorus ligationfor 6 hours and it was as effective as theH2- antagonist cimetidine in theseexperiments (21). Further studies showedthat meciadanol promotes the healing ofgastric ulcers induced by restraint inrats (22). The healing took placesignificantly faster in the rats receivingmeciadanol than in control rats. It alsoproduced a significant synergistic actionwhen used in combination with cimetidinein different models of experimentalulceration in rats.

Meciadanol had undergone detailedpreclinical toxicity studies. The acute,

------~ ---


subacute and chronic toxicity studies inrats, administration by intravenous dose indogs and the local tolerance studies inrabbits showed that the compound was safefor conducting the clinical investigations byoral route in human beings. It has beenfound to be devoid of any teratogenicpotential in rats and rabbits. It did notproduce any mutagenic effect in the Amestest and in the cytogenic test done on bonemarrow cells of mouse. It was also foundinactive in the carcinogenicity test on BALP3T3 mouse cells in culture (14).

Pharmacokinetic studies on meciadanolshow that the orally administered drug iswell absorbed and gradually excreted inurine and faeces during a period of 72 hoursIn rats, mice and marmosets. It ismetabolized by methylation of thehyroxyphenol groups of the B nucleus in3,3' dimethoxy 5,7, 4'-trihydorxy flavan.This metabolite is then conjugated andexcreted in the urine and bile (15).

No breakdown products of meciadanol orits principal metabolite by the intestinaltract microflora due to ring fission havebeen observed in any of the species testedbecause the substitution in position 3probably stabilises the molecule. There wasalso no evidence of the demethylation of thecompound at any stage of the metabolism.The fact that it is not demethylated in vivomeans that its action is not due to itsconversion to (+)-cyanidanol-3 in the body.This stability of ether link in position 3 isalso likely to persist in man (15, 16).

The results of preliminary clinical trialsshowed a significant potential for developingit into a promising anti-ulcer drug. It.


showed protective effect against aspirininduced irritation of the human gastricmucosa as demonstrated by measuring thegastric potential difference (23) accordingto the method of Laule et al (24). Oralpretreatment with 250-1000 mg ofmeciadanol reduced the degree of irritationof gastric mucosa in a dose dependentmanner. In volunteers treated withmeci ad an ol , the histamine content wassignificantly reduced in the fundus, corpusand antrum of the stomach (12). In anotherstudy on the effect of meciadanol on gastricsecretion and aspirin induced gastricmucosal injury in humans, Konturek et al(25) found that meciadanol did not affecteither basal or pentagastrin stimulatedgastric acid secretion or pepsin secretionand did not produce any endoscopic orhistological changes in the stomach orduodenum. Nevertheless, it preventedaspirin-induced microbleeding and aspirin-induced DNA loss suggesting that gastricmucosal histamine is involved in themucosal inju r y caused by a sp i r i n .Subsequently, Konturek et al (26) haveestablished a true cytoprotective effect ofmeciadanol on ethanol and aspirin inducedgastric mucosal damage in rats which wascomparable to that of 16, 16-dimethyl PGE

2.

It was neither mediated by the reduction ofgastric or pepsin activity nor by enhancingthe endogenous muscosal PGI2 levels.

Inspite of its highly effective anti-ulcerprofile and unique mode of action, thiscompound could not be introduced intherapeutics as an useful anit-ulcer drug. Ascatechins were shown to produce hemolyticanemias, further attempts to developmeciadanol and other potential compoundsas anti-ulcer drugs were given up.


However, these studies point towards astrong possibility of finding out a safe andeffective flavonoid possessing histidinedecarboxylase inhibitory and anti-ulceractivity in future (22). Recent publicationsof Murakami et al (27) and Alarcon de laLastra et al (28) reveal the property ofgastric H+, K+-ATPase inhibition incatechins and that of lipoxygenase inhibitionin silymarin respectively. These findingsalso support the above contention andprovide impetus for further indepth studieson anti-ulcer profiles of flavonoids. Anotherrecent publication reveals the dosedependent reduction in gastric mucosaldamage and the mucosal content of plateletactivating factor by flavonols like rutin,quercetin and kaempferol (29).

Sofalcone

In Chinese medicine, a crude drug calledKohzukon (Sophora subprostrata Chun etT. Chen) has been used in the treatment ofdigestive diseases. It has been reported thatsophoradin, a compound isolated from theroot of this ancient Chinese plant exhibitsanti-ulcer activity in experimental models.One of the sophoradin derivatives, anisoprenyl flavonoid known as sofalcone (2'-carboxy-methoxy-4-4'-bis (3-methyl-2-butenyloxy) - chalcone has been extensivelystudied for its anti-ulcer potential. Sofalconeprevents acute gastric ulceration induced byacidified aspirin, water immersion andrestraint ulcers (30) and has a cytoprotectiveeffect against 0.6 N HCI and abosluteethanol induced mucosal lesions in ratstomach (30, 31, 32) and taurocholateinduced gastritis in rats (33). Prostaglandinshave been shown to be involved in its anti-ulcer and cytoprotective effects (30). It

348 Parmar and Parmar Indian J Physiol Pharmacol 1998; 42(3)

TABLE I : Naturally occurring and semisynthetic flavonoids with significant anti-ulcer activity.

Plants ReferencesEffective compounds Models studied

Sophora Subprostata 39

Glycyrrhiza glabra

Silybim marianum

Rhamnus procubens

Anacardium occidentaleLinn and other sources

Erica andevalensis

Genista ru rnel ica

Sideritis leucantha

Eucalyptus maculataHook; Citrus paradisiMacfad

Aurantii frustusimmaturus

Dittrichia Viscosa

Cistus incanus

Sophoradin Experimental gestriculcers in rats andguinea pigs, Pylorusliga ted ra ts

Now in clinical use 37

38

28

40

11, 16, 17,20, 21, 22,23, 24, 25, 26

27

24,25

41

42, 43

44

45

46, 47

48

49

50

Sofalcone(Semisyn the tic)

Hydroxychalcones HCI-ethanol, water-immersion and aceticacid induced gastriculcers in rats

Silymarin Ethanol, cold-restraint,pylorus ligration in rats

Pylorus ligation andrestraint in rats,histamine in guineapigs

Pylorus ligation, NSAIDs inrats. Histamine in guinea pigs

Kaempferol

Catechins

(+)-Cyandidanol-3CatechinsMeciadanol(Semisyn thetic)

Flavonoid Extract

Gastric H+, K+ ATPaseinhibitionUndergone clinical trials

Amentoflavone

Cold stress, Pylorus ligation,Ethanol in ratsPylorus ligation,restraint in rats:histamine in guineapigs

Experimental gastric ulcersin rats

Genistine(Total flavonoidmixture)

Hypolaetin-8-0-beta-D-glucoside

Quercetin,Naringenin

Ethanol and aspirin in rats

Cold + restraint andpylorus ligation in rats

Nobiletin andMarmin

Ethanol and aspirin in rats

Flavonoidfraction

Ethanol, HCI, Hypertonicsaline and indomethacinin rats

Flavonoidextract

HCI, ethanol indomethacin,reserpine and serotoninin rats.


inhibits the activity of PG metabolizingenzyme 15-hydroxy-PG-dehydrogenase andelevates the PGE2 content of the gastricmucosa in rats subjected to absolute ethanolinduced gastric mucosal damage andtaurocholate induced gastritis (30, 33).

Sofalcone has been clinically tried inJapan for the treatement of gastroduodenalulcers by a number of workers (34-37). Ithas been found particularly useful inaccelerating the healing of gastric ulcerswhich were shown to be accompanied by adeficiency of PG biosynthesis in gastricmucosa.

Hydroxychalones

Taking a lead from the studies ofsofalcone, Yamaoto et al (38) studied thegastroprotective effect of a number ofhydroxych!llcones obtained from variousplants against necrotizing agents - inducedgastric ulcers in rats viz. RCI-ethanol andNaOH and those induced by waterimmersion stress and acetic acid. Amongstthe nine hydroxychalcones tested by


them, 2', 4' - dihydroxychalcone appears tobe most p r om i s in g compound forfurther development as an anti-ulceragent.

A number of publications have appearedduring the last two decades describing theanti-ulcer potential of flavonoids orflavonoidal extracts from plants. Someimportant reports have been summarized inTable 1.

CONCLUSION

During the recent years flavonoids havebeen the most widely studied naturalcompounds for their anti-ulcer potential.Both meciadanol and sofalcone have beenstudied for their clinical effectiveness andwere found effective in the clinical trials.Though these compounds could not bedeveloped and marketed as effective anti-ulcer agents, they have opened new vistasin ulcer research and pharmacologists arestill working to find out an effective andsafe anti-ulcer drug from this class ofnaturally occurring compounds.

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ANTI-ULCER POTENTIAL OF FLAVONOIDS