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The effect of ellagic acid (EA), a naturally occurring plant phenol, on the metabolism, DNA binding and DNA adduct formation of N-nitrosobenzylmethylamine (NBMA) in cultured explants of rat esophagus was investigated. Explants were incubated in medium containing EA at non-toxic concentrations of 10, 50 and 100 microM for 16 h, followed by the addition of 1 microM [3H]NBMA and EA for 12 h. Explant DNA was isolated by phenol extraction and hydroxylapatite chromatography, and benzaldehyde formation was determined by HPLC analysis of the culture medium. EA produced a significant inhibition in the total covalent binding of NBMA metabolites to DNA and in the production of benzaldehyde in the medium. After acid hydrolysis of the isolated DNA, the NBMA--DNA adducts were separated by HPLC. EA caused a dose-dependent decrease in the formation of N7-methylguanine and O6-methylguanine adducts. These results suggest that EA inhibits both the metabolism of NBMA and the binding of NBMA metabolites to DNA in cultured rat esophagus.

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Ellagic acid (EA), a plant phenol found in various fruits and nuts, was examined for its ability to inhibit aflatoxin B1 (AFB1) mutagenesis in strain TA 100 of Salmonella typhimurium. In the presence of rat liver S-9 microsomal preparation, EA (1.5 microgram/plate) inhibited the number of mutations induced by AFB1 (0.5 microgram/plate) by 50%. EA at a dose of 1000 micrograms/plate inhibited the mutation frequency by greater than 90%. EA was also tested for its ability to inhibit the DNA binding and adduct formation of AFB1 in cultured explants of rat trachea and human tracheobronchus. Explants were incubated in medium containing EA at concentrations of 10, 50 and 100 microM for 16 h followed by the addition of 1 microM [3H]AFB1 and EA for 24 h. DNA was isolated by phenol extraction and hydroxylapatite chromatography. EA caused a dose-dependent inhibition in the covalent binding of AFB1 to the DNA of both the rat trachea (9-57% inhibition) and human tracheobronchus (24-79% inhibition). After acid hydrolysis of the isolated DNA, the AFB1-DNA adducts were separated by h.p.l.c. In tissues from both species, the major AFB1- DNA adducts were AFB1-N7-Gua [8,9-dihydro-8-(N7-guanyl)-9-hydroxyAFB1] and AFB1-N7-FaPyr (major) [8,9-dihydro-8- (2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl formamido)-9-hydroxyAFB1], and the formation of these adducts was reduced by 28-76% in the presence of EA. These data indicate that EA has the potential to act as a naturally occurring inhibitor of AFB1-related respiratory damage in rats and in humans.

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Arecoline, a major alkaloid present in betel nut, was administered daily by gavage feeding to Swiss male and female mice at a dose of 1 mg/day/mouse five times a week, either alone or in combination with KNO3 or KNO3 + lime. Swiss mice of both sexes kept on a vitamin B complex-deficient diet were tested in a similar manner and compared with those receiving a normal diet. In the mice receiving a normal diet it was observed that arecoline induced tumors in 40% of males but failed to produce tumors in any of the females. Arecoline tumorigenicity in females was evident only when they received a vitamin B-deficient diet. Arecoline tumorigenicity was not evident in males when they were treated simultaneously with KNO3 + lime and kept on a normal diet. However, the same treatment administered to male mice kept on a vitamin B complex-deficient diet induced tumors in 39%.

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Betel quid ingredients--betel nut, betel leaf, lime, catechu and tobacco--were tested separately and in various combinations for carcinogenicity, using hamster cheek pouch as the experimental site. The four modes of administration used were (1) tri-weekly painting of the cheek pouch with aqueous extracts of test materials, (2) deposition of replaceable wax pellets containing the test material, (3) gelatin capsules containing the powdered material and (4) insertion of natural material into the pouch for trauma and direct exposure. Untreated controls and standard carcinogen DMBA-treated controls were also maintained. A total of 317 young adult golden Syrian hamsters (Mesocricetus auratus) used for the experiments were killed in two age groups: 6-12 months and 13-24 months, only when signs of general debility were observed. In the untreated controls, animals were free of any malignancy. In the experimental series, various betel quid ingredient combinations under test induced both oral and gastric lesions ranging from massive atypia and precancerous lesions to frank carcinomas. Maximum lesions were observed in the groups receiving betel nut, lime and tobacco combinations and in the polyphenol fraction of betel nut containing major tannins. The mode of administration of test material resulted in distinct differences; tri-weekly paintings giving oral lesions in the range of 22-23% and gastric lesions 39-48%; the same material given either through the replaceable gelatin capsule or in natural form induced 69% oral lesions and 63 to 82% gastric lesions. Overall evaluation of the data of all the four series confirms the potent carcinogenicity of betel nut, particularly its tannin-containing polyphenolic fraction and its combination with lime and tobacco. Maximum oral lesions induced in the hamsters by continuous exposure to capsules and natural material, highlight the direct relationship of frequency of chewing in habitual chewers with oral carcinogenesis. The high incidence of gastric (forestomach) lesions invites special attention.

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Male mice of inbred strains Swiss and C17 were fed daily 5 times a week by intragastric tube 0.1 ml of betel-nut aqueous extract, betel-leaf aqueous extract and the polyphenol fraction of betel nut. Male mice of corresponding strains fed 0.1 ml of distilled water served as controls. Treated and control mice were kept under observation and killed when moribund. Betel-nut aqueous extract induced tumours of the gastrointestinal tract in 58% Swiss mice and 25% C17 mice. The polyphenol fraction by the same route induced tumours at other sites in 17% of the mice. Betel-leaf aqueous extract failed to induce any tumour in the treated mice, which supports an earlier report of the lack of any carcinogenic principle in betel leaf, an essential constituent of betel quid. Results are discussed in relation to the relevant literature.

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