FEATURE Ellagic Acid, an Anticarcinogen in Fruits, Especially in Strawberries: A Review John L. Maasl and Gene J. Galletta2 Fruit Laboratory, U.S. Department of Agriculture, Agricultural Research Service, Beltsville, MD 20705 Gary D. Stoner3 Department of Pathology, Medical College of Ohio, Toledo, OH 43699 The various roles of ellagic acid as an an- digestibility of natural forms of ellagic acid, Mode of inhibition ticarcinogenic plant phenol, including its in- and the distribution and organ accumulation The inhibition of cancer by ellagic acid hibitory effects on chemically induced cancer, or excretion in animal systems is in progress appears to occur through the following its effect on the body, occurrence in plants at several institutions. Recent interest in el- mechanisms: and biosynthesis, allelopathic properties, ac- lagic acid in plant systems has been largely a. Inhibition of the metabolic activation tivity in regulation of plant hormones, for- for fruit-juice processing and wine industry of carcinogens. For example, ellagic acid in- mation of metal complexes, function as an applications. However, new studies also hibits the conversion of polycyclic aromatic antioxidant, insect growth and feeding in- suggest that ellagic acid participates in plant hydrocarbons [e.g., benzo (a) pyrene, 7,12- hibitor, and inheritance are reviewed and hormone regulatory systems, allelopathic and dimethylbenz (a) anthracene, and 3-methyl- discussed in relation to current and future autopathic effects, insect deterrent princi- cholanthrene], nitroso compounds (e.g., N- research. ples, and insect growth inhibition, all of which nitrosobenzylmethylamine and N -methyl- N- Ellagic acid (C14H6O8) is a naturally oc- indicate the urgent need for further research nitrosourea), and aflatoxin B1 into forms that curring phenolic constituent of many species to understand the roles of ellagic acid in the induce genetic damage (Dixit et al., 1985; from a diversity of flowering plant families. plant. Teel et al., 1985; Mandal et al., 1987, 1988). Interest in ellagic acid has increased greatly Carcinogenic and mutagenic factors, whether b. Carcinogen detoxification by stimulation during the last decade due to its effectiveness natural or products of industry, are ubiquitous of enzyme (e.g., glutathione s-transferase) ac- as an antimutagen and anticarcinogen and its in our environment. We may minimize our tivity is increased toward benzo(a) pyrene-4,5- potential as an inhibitor of chemically in- exposure to these carcinogens, but it is un- oxide and l-chloro-2,4-dinitrobenzene sub- duced cancer. Much has been learned since likely that they will ever be eliminated. Many strates in mice (Das et al., 1985). 1980 concerning the clinical attributes of el- efforts have been directed toward improving c. Binding to reactive metabolic forms of lagic acid, but relatively little is known about dietary habits to minimize cancer risk. In ad- the carcinogen to form a harmless complex the physiological, genetic, and ecological dition, the identification of naturally occurring that is incapable of reacting with cellular aspects of ellagic acid and its naturally oc- anticarcinogens and antimutagens present in DNA, i.e., acts as a scavenger. Ellagic acid curring derivatives in the plant. We know the diet is becoming increasingly important. A reacts with benzo (a) pyrene diol epoxide by that ellagic acid is present in a wide variety comprehensive knowledge of the cancer inhib- taking a sterically favorable position to form of plants and its presence or absence maybe itory properties of anticarcinogens necessitates a covalently linked product in which the re- significant taxonomically, but we are only an understanding of their action, and their active epoxide ring of the pyrene is opened, beginning to notice intraspecific variation. physiological roles in plants. rendering the carcinogen harmless (Sayer et Ellagic acid exists in plants in a great many al., 1982). derivative forms that differ in volubility, mo- d. Occupation of sites in DNA that might bility, and reactivity in plant as well as in Ellagic acid: Anticarcinogen/antimutagen otherwise react with carcinogens or their me- animal systems. Research has progressed at tabolizes. Ellagic acid inhibited the binding a rapid rate among medical research pro- Ellagic acid has shown promise as an in- hibitor of chemically induced cancer in in- of N -methyl- N -nitrosourea to salmon sperm grams studying ellagic acid as a potential 6 vivo studies with rats and mice and in in- DNA by reacting with the O position in anticarcinogen or in blood clotting research. quanine and preventing methylation at that Exploring dietary sources of ellagic acid, the vitro studies with rat, mouse, and human tis- sue explants (Table 1). Antimutagenicity site (Dixit and Gold, 1986; Teel, 1986). studies are generally done by assessing the Received for publication 10 Apr. 1990. The cost inhibition by ellagic acid of potentially mu- Conflicting evidence of publishing this paper was defrayed in part by tagenic chemicals in cultures of the bacter- the payment of page charges. Under postal regu- ium Salmonella typhimunium. Although ellagic acid shows promise as lations, this paper therefore must be hereby marked Data have been reviewed on the effective- an inhibitor of chemically induced cancer, advertisement solely to indicate this fact. lPlant Pathologist. ness of ellagic acid as an anticarcinogen and conflicting data have been presented in the 2Geneticist. antimutagen and on its mode of action as an literature on its effectiveness in preventing 3Medical Research Pathologist and Director of Ex- inhibitor of chemically induced cancer (De carcinogenesis or even DNA-adduct forma- perimental Pathology. Flora and Ramel, 1988; Hayatsu et al., 1988; tion (Table 1). The high affinity of the strongly Stoner, 1989). nucleophilic 4-OH group for electrophilic 10 HORTSCIENCE, VOL. 26(l), JANUARY 1991 Table 1. Anticarcinogenic and antimutagenic activity of ellagic acid. Biosynthesis Carcinogen Tissue: donor Response z Reference Chemically, ellagic acid (Fig. 1) is 2,3,7,8- tetrahydroxy[l]benzo-pyrano-[5,4,3-cde] [1] Benzo (a) pyrene Skin; rat AC Del Tito et al., 1983 Lung explants; mouse AC Dixit et al., 1985; benzopyran-5,10-dione, C14H6O8, with a mo- Teel et al., 1985 lecular weight of 302.19. It can be prepared Skin; mouse AC Chang et al., 1985 from natural sources (Eucalyptus bark, wal- Skin explant; mouse AC Mukhtar et al., 1984b nuts, etc.) by sodium persulfate oxidation of Lung, skin; mouse AC Lesca, 1983 gallic acid or by acid hydrolysis of crude tan- Lung explant; human AC Teel et al., 1986a, 1986b nin (Zee-Cheng and Cheng, 1986). In nature, Salmonella (Ames) test AM Wood et al., 1982 ellagic acid may occur in free form, but more Lung, skin; mouse NE Smart et al., 1986a commonly in the form of ellagitarmins as es- Aflatoxin B Salmonella (Ames) test AM San and Chan, 1987; 1 ters of the diphenic acid analog on glucose. Tracheobronchial Mandal et al., 1987 explants; rat, human AC Mandal et al., 1987 Ellagic acid is formed by oxidation and 7,12-Dimethylbenz dimerization of gallic acid; thus, it is a di- (a) anthracene Mammary; rat NE Singletary and Liao, 1989 lactone of the dimer of gallic acid. Oxidation Nitroso compounds Rat AC Barth and Fox, 1988; is hastened by alkaline conditions, whereas Mandal et al., 1988, 1990 hydrolysis and lactonization is favored by Salmonella (Ames test) AM Dixit and Gold, 1986 acidic conditions (Tulyathan et al., 1989). 3-Methylcholanthrene Skin; mouse AT Mukhtar et al., 1984a, 1986 Ishikura et al. (1984) postulate two pathways Skin; mouse NE Smart et al., 1986b for gallic acid formation; through B-oxida- N -2-fluorenvIacetamide Liver: rat AC Tanaka et al., 1988 tion of phenylpropanoid and through dehy- zAC = anticarcinogenic effect; AM = antimutagenic effect; AT = antitumorigenic; NE = no AC or drogenation of shikimic acid in Rhus and Acer. AM effects detected. The preferential pathway may be determined by leaf age, although temperature studies were metabolizes that are non-DNA-reactive sub- clotting, ellagic acid activates the Hageman not undertaken. The pathway from phenyl- stances may effectively remove ellagic acid clotting factor (Factor XII) in blood (Bock alanine to cinnamic acid via phenyllactic acid from biological systems and prevent it from et al., 1981). Ellagic acid is used widely in is a possible pathway in strawberries. Activ- acting as an anticarcinogen (Hayatsu et al., blood research to study factors affecting ity of the delaminating enzyme phenylalanine 1988). Absorption of ellagic acid into the clotting, or thrombosis. It also may have some ammonia-lyase (PAL) corresponds to the ac- body from a dietary source also appears to hypotensive (lowering blood pressure) and cumulation of anthocyanin in strawberry fruit be limited. Ellagic acid fed orally to mice sedative effects according to preliminary re- (Given et al., 1988; Hyodo, 1971) and of was found to be poorly absorbed and is elim- search with rodents (Bhargava et al., 1968). flavonoids and cinnamic acids in strawberry inated as free ellagic acid and in conjugated leaf disks (Creasy, 1971); however, the re- forms (Tee] and Martin, 1988; Smart et al., lationship has not been determined between 1986a), which may prevent tissues from at- Occurrence in plants PAL activity and ellagic acid production. taining sufficiently high concentrations for it Tannins and associated polyphenols in plant to be effective as an in-vivo anticarcinogen. Ellagic acid is a naturally occurring phe- extracts have been widely studied for their Synthetic lipophilic derivatives of ellagic acid, nolic constituent of many flowering plant medicinal and antimutagenic and anticarcin- especially 3- o -decylellagic acid, have greater species (Bate-Smith, 1961 b). In the family ogenic properties (Hayatsu et al., 1988; Ito affinities for lung and other tissues than has Rosaceae (Bate-Smith, 1961a) and in the Fa- et al., 1989; Iwu and Anyanwu, 1982 Okuda ellagic acid proper (Smart et al., 1986a). gaceae (Giannasi and Niklas, 1981), ellagic et al., 1989; Sigman et al., 1984).