Electrophysiologic characteristics of the atrium during chronic atrial fibrillation in man

Acorn tannins may affect food preferences and foraging strategies of squirrels through effects on acorn palatability and digestibility and squirrel physiology. Captive eastern gray squirrels (Sciurus carolinensis) were fed 100% red oak (Quercus rubra) or white oak (Quercus alba) acorn diets to determine effects on intake, digestion, and detoxification activity. Red oak acorns had higher phenol and tannin levels, which may explain the lower dry matter intakes and apparent protein digestibilities and the higher glucuronidation activities observed in squirrels. Although the white oak acorn diet had lower apparent protein digestibilities than the reference diet, it did not suppress dry matter intake for a prolonged period or stimulate glucuronidation. Negative physiological effects of a 100% red oak acorn diet suggest gray squirrels may require other foods to dilute tannin intake and provide additional nutrients. To distinguish the roles of different tannin types in the observed effects of acorn diets on squirrels, squirrels were fed rat chow containing no tannins, 4% or 8% tannic acid (hydrolyzable tannin), or 3% or 6% quebracho (condensed tannin). Apparent protein digestibilities were reduced by tannic acid and quebracho diets. Only the 8% tannic acid diet tended to increase glucuronidation. Specific effects of tannins may largely depend on tannin type, composition, and source and on other nutritional and physiological factors.     

Mechanism of inhibition of tannic acid and related compounds on the growth of intestinal bacteria

Tannic acid, propyl gallate and methyl gallate, but not gallic acid, were found to be inhibitory to the growth of intestinal bacteria Bacteroides fragilis ATCC 25285, Clostridium clostridiiforme ATCC 25537, C. perfringens ATCC 13124, C. paraputrificum ATCC 25780, Escherichia coli ATCC 25922, Enterobacter cloacae ATCC 13047, Salmonella typhimurium TA98 and S. typhimurium YG1041 at 100-1000 microg/ml in culture broth. Neither Bifidobacterium infantis ATCC 15697 nor Lactobacillus acidophilus ATCC 4356 was inhibited by any of the above compounds up to 500 microg/ml. Tannic acid has a much greater relative binding efficiency to iron than propyl gallate, methyl gallate or gallic acid. The inhibitory effect of tannic acid to the growth of intestinal bacteria may be due to the strong iron binding capacity of tannic acid; whereas the effect of propyl gallate and methyl gallate probably occurs by a different mechanism. The growth of E. coli was restored by the addition of iron to the medium after the precipitate caused by tannic acid was removed. Neither B. infantis nor L. acidophilus require iron for growth. This probably contributes to their resistance to tannic acid. Because tannins are abundant in the human diet, tannins may affect the growth of some intestinal bacteria and thus may have an impact on human health.     

Interaction of tannin with human salivary proline-rich proteins

Tannins are polyphenolic compounds, widely distributed in plant-based foods, which have harmful effects on animals including humans. Salivary proline-rich proteins (PRPs) may act as a defence against tannins by forming complexes with them and thereby preventing their interaction with other biological compounds and absorption from the intestinal canal. The aim here was to compare the ability of members of the family of human PRPs to form insoluble complexes with tannin and to assess the stability of such complexes under conditions similar to those in the alimentary tract. Basic PRPs (BPRPs), which have no other known biological functions, were very effective in forming insoluble complexes with both condensed tannin and tannic acid. Practically no tannin bound to acidic PRPs (APRPs) and glycosylated PRPs (GPRPs), suggesting that tannin in the diet would not affect their biological activities. There were only small differences in the tannin-precipitating ability of various BPRPs of different sizes or sequences, indicating that, although there is considerable phenotypic variation of PRPs, it is not likely to cause marked individual variation in tannin-binding ability. Tryptic digestion of an APRP led to a marked increase in tannin binding to the resulting proline-rich peptides, supporting observations in other studies that there may be an interaction between the proline-poor N-terminal and the proline-rich C-terminal regions in native APRPs, which inhibits the biological activities of the proteins. Deglycosylation of a GPRP also led to a dramatic increase in tannin-binding ability, showing that the carbohydrate side-chains prevent binding of tannin. Most of the condensed tannin-PRP complexes remained insoluble under conditions similar to those in the stomach and small intestine, supporting the proposal that PRPs act as a defence against tannin.     

Tannic acid and oxidized tannic acid on the functional state of rat intestinal epithelium

Diets containing tannic acid at the level of 3% of dry matter were fed to rats in order to ascertain the origin of fecal nitrogen and the effect of tannic acid on the intestinal mucosa. At the same time in order to explain the effect of oxidation of tannins, we administered diets containing oxidized tannic acid or tannic acid associated with an antioxidizer (sodium sulfite) at the level of 1% of dry matter. The increased excretion of sialic acid and glucosamine during ingestion of tannic acid indicated that the excess of fecal nitrogen mainly corresponds to the mucus hypersecretion observed by histology. Fecal analysis revealed perturbations in movements of water and ions. The study of the metabolic activity of isolated enterocytes and the activity of some enzymes in a homogenate of these cells showed an inhibition of oxygen consumption and succinic dehydrogenase activity. Addition of reducing agent (sodium sulfite) to the diet had little effect on the action of tannic acid; but previous oxidation of the tannin reduced the effects observed, particularly in the case of fecal nitrogen loss.     

Natural dietary polyphenolic compounds cause endothelium-dependent vasorelaxation in rat thoracic aorta

This study investigated the possible active principles which support the endothelial nitric oxide-dependent relaxation produced by red wine and other plant polyphenolic compounds in thoracic aorta from male Wistar rats (12-14 wk old). Relaxation experiments were recorded isometrically on vessels precontracted with norepinephrine. Ten different chromatographic fractions (3-18 mg) isolated from red wine polyphenolic compounds (RWPC) and some available defined polyphenols (10-15 mg) were tested. Fractions enriched into either anthocyanins or oligomeric condensed tannins exhibited endothelium-dependent vasorelaxant activity (maximal relaxation in the range of 59-77%) comparable to the original RWPC. However, polymeric condensed tannins elicited a weaker vasorelaxant activity than the original RWPC (maximal relaxation ranged between 20-47%, P < 0.01). Moreover, the representative of either phenolic acid derivatives (benzoic acid, vanillic acid, gallic acid), hydroxycinnamic acid (p-coumaric acid, caffeic acid) or the flavanol [(+)-epicatechin] classes failed to induce this type of response. Among the anthocyanins, delphinidin (maximal relaxation being 89%), but not malvidin or cyanidin, showed endothelium-dependent vasorelaxation. These results show that anthocyanins and oligomeric-condensed tannins exhibited a pharmacological profile comparable to the original RWPC. These compounds may be involved in the reduction of cardiovascular mortality related to the presence of wine, fruits and vegetables in the diet.     

Janus carcinogens and mutagens

Janus carcinogens are carcinogenic agents that, under differing conditions of cell type or dose, can instead act as anticarcinogens. Studies by Haseman and Johnson [J.K. Haseman, F.M. Johnson, Analysis of rodent NTP bioassay data for anticarcinogenic effects, Mutat. Res. , 350 (1996) 131-142], have demonstrated that many chemicals that are carcinogenic for one tissue type can have anticarcinogenic action on another tissue type. As Magni et al. [G.E. Magni, R.C. von Borstel, S. Sora, Mutagenic action during meiosis and antimutagenic action during mitosis by 5-aminoacridine in yeast, Mutat. Res., 1 (1964) 227-230] have shown in 1964, this principle holds true for chemical mutagens as well, that is 9-aminoacridine is an antimutagen in the vegetative cell and a mutagen in the sporulating cell. The conclusion can be drawn that two established carcinogens, tobacco and ionizing radiation, are indeed Janus carcinogens. In their review of 'ambiguous carcinogens' (their name), Weinberg and Storer [A.M. Weinberg, J.B. Storer, Ambiguous carcinogens and their regulation, Risk Anal., 5 (1985) 151-156], pointed out that tobacco can be classified as an ambiguous carcinogen. The strong carcinogenicity and anticarcinogenicity of tobacco smoke and/or tobacco itself (i.e., chewing tobacco) may be due to components in the mixture, not that of a single carcinogenic chemical that also may be anticarcinogenic. Kondo [S. Kondo, Health Effects of Low-Level Radiation, Kinki Univ. Press, Osaka, Japan and Medical Physics Publishing, Madison, WI, 1995, 213 pp.] has compiled data that demonstrate that human populations who survive exposures to ionizing radiation generally live longer and have less cancer than unirradiated human populations, and this Janus phenomenon goes beyond the more trivial concept of increased sensitivity to radiation of rapidly dividing tumor cells. Thiabendazole is an interesting compound in that it is both aneugenic and antimutagenic, and yet it does not appear to be a carcinogen or a mutagen. It is discussed here because aneugenesis and antimutagenesis are at extremes of the mutagenic spectrum. In general, mutagenic or carcinogenic actions usually are at least partially understood at a molecular level, whereas antimutagenic and anticarcinogenic actions usually are not. It is possible there may be numerous specific mechanisms underlying the Janus activity of different chemicals.     

Mutations induced by gamma-irradiation of M13 bacteriophages containing single-stranded DNA

Astringent compounds were applied to oral epithelium of the clawed toad, Xenopus laevis, and rapidly rising and highly sensitive responses could be recorded from the whole glossopharyngeal nerve, but not at all from the trigeminal nerve. The response to 10 mM tannic acid decreased progressively with repetitive application. These responses to tannic acid, however, recovered completely by treating with chemicals capable of forming strong hydrogen and hydrophobic bonds. These chemical bondings are generally recognized as a model for polyphenol (tannin)-protein interactions based on physico-chemical measurements in vitro. The high affinities of these chemicals for tannic acid may be effective in releasing both bonds in the interaction of tannic acid with the receptor molecules. Our results provide in vivo evidence for this model.     

1 - 1. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl)indole. [Part I]

Indole-3-carbinol (I3C) (2) is produced endogenously from naturally occurring glucosinolates contained in a wide variety of plant food substances including members of the family Cruciferae, and particularly members of the genus Brassica, whenever they are crushed or cooked. The acid environment of the gut very facilely converts it into a range of polyaromatic indolic compounds, e.g. (3, 4,5), which appear to be responsible for many of the physiological effects observed following the ingestion of these foods. 3-(Methoxymethyl)indole (6) is formed with great ease whenever 2 contacts methylating agents, including methanol, and it is often found as a contaminant of 2. This contamination is often not recognized or easily removed because of the great similarities of the two in melting points and solubilities. However, their biological properties are essentially identical. These so-called chemopreventive compounds are important because of their enzyme induction and suppression, mutagenic, carcinogenic and, particularly, antimutagenic and anticarcinogenic properties. The natural occurrence, formation, preparation, identification, separation, quantification, chemical transformations and general toxicological properties of these substances are critically reviewed in detail in this paper of 146 references, the first of two parts. The enzyme induction and suppression, mutagenic, antimutagenic, mutagenic, anticarcinogenic and carcinogenic effects will be published later as Part II. At the present time it appears that these have considerable potential as natural prophylactic anticancer agents against certain common neoplasms, especially inasmuch modern diets are increasingly deficient in these vegetable-derived substances.     

1. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl)indole. [Part II]

Indole-3-carbinol (I3C) (2) is produced endogenously from naturally occurring glucosinolates contained in a wide variety of plant food substances including members of the family Cruciferae, and particularly members of the genus Brassica, whenever they are crushed or cooked. The acid environment of the gut very facilely converts it into a range of polyaromatic indolic compounds, e.g. (3, 4,5), which appear to be responsible for many of the physiological effects observed following the ingestion of these foods. These so-called chemopreventive compounds are important because of their enzyme induction and suppression, mutagenic, carcinogenic and, particularly, antimutagenic and anticarcinogenic properties against a variety of classes of carcinogens. These properties as well as other miscellaneous properties of these substances are critically reviewed in detail in this paper of >170 references, the second of two parts. At the present time it appears that I3C and its congeners have considerable potential as natural prophylactic anticancer agents against certain common neoplasms, especially inasmuch modern diets are increasingly deficient in these vegetable-derived substances. A short general assessment of the substantial potential of the title compounds concludes the review.     

Chemopreventive agents: protease inhibitors

Certain protease inhibitors, called the anticarcinogenic protease inhibitors in this review, are capable of preventing carcinogenesis in a wide variety of in vivo and in vitro model systems. The anticarcinogenic protease inhibitors are extremely potent agents with the ability to prevent cancer, with some unique characteristics as anticarcinogenic agents. The anticarcinogenic protease inhibitors have the ability to irreversibly suppress the carcinogenic process. They do not have to be continuously present to suppress carcinogenesis. They can be effective when applied in both in vivo and in vitro carcinogenesis assay systems at long time periods after carcinogen exposure, and are effective as anticarcinogenic agents at extremely low molar concentrations. While several different types of protease inhibitors can prevent the carcinogenic process, the most potent of the anticarcinogenic protease inhibitors on a molar basis are those with the ability to inhibit chymotrypsin or chymotrypsin-like proteases. The soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI), is a potent chymotrypsin inhibitor that has been extensively studied for its ability to prevent carcinogenesis in many different model systems. Much of this review is focused on the characteristics of BBI as the anticarcinogenic protease inhibitor, as this is the protease inhibitor that has risen to the human trial stage as a human cancer chemopreventive agent. Part of this review hypothesizes that the Bowman-Birk family of protease inhibitors plays a role in plants similar to that of alpha1-antichymotrypsin in people. Both BBI and alpha1-antichymotrypsin are potent inhibitors of chymotrypsin and chymotrypsin-like enzymes, are highly anti-inflammatory, and are thought to play important roles in the defense of their respective organisms. It is believed that BBI will be shown to play a major role in the prevention and/or treatment of several different diseases, in addition to cancer.     

Iron staining of the acquired enamel pellicle after exposure to tannic acid or chlorhexidine: preliminary report

Extrinsic discoloration of teeth following a large consumption of tannin-containing beverages or a prolonged use of chlorhexidine mouthrinses is a well known observation. Tannins as well as chlorhexidine are denaturing agents. Based on preliminary studies revealing the presence of iron in chlorhexidine discolored pellicle material, the ability of iron to stain the integument after pretreatment with the two denaturants was studied in a human model. The denaturing effect of an acidic environment was also included. Enamel slabs fixed to acrylic appliances were carried in the oral cavity and alternately exposed to the test solutions in different sequences in vitro. Pretreatment with chlorhexidine or tannic acid led to marked discoloration upon iron application during 5-d tests, whereas the compounds individually had no such effect. A large content of the metal was found in the stained material. Stannous fluoride appeared to reduce the formation of the pigments, and strong oxidation completely bleached the established color. Possible mechanisms underlying the phenomena observed are discussed.     

Effect of dietary phytochemicals on cancer development (review)

Vegetables, fruits, and whole grains contain a wide variety of phytochemicals that have the potential to modulate cancer development. There are many biologically plausible reasons why consumption of plant foods might slow or prevent the appearance of cancer. These include the presence in plant foods of such potentially anticarcinogenic substances as carotenoids, chlorophyll, flavonoids, indole, isothiocyanate, polyphenolic compounds, protease inhibitors, sulfides, and terpens. The specific mechanisms of action of most phytochemicals in cancer prevention are not yet clear but appear to be varied. Considering the large number and variety of dietary phytochemicals, their interactive effects on cancer risk may be extremely difficult to assess. Phytochemicals can inhibit carcinogenesis by inhibiting phase I enzymes, and induction of phase II enzymes, scavenge DNA reactive agents, suppress the abnormal proliferation of early, preneoplastic lesions, and inhibit certain properties of the cancer cell.     

The evidence of clonal evolution with monosomy 7 in aplastic anemia following granulocyte colony-stimulating factor using the polymerase chain reaction

The polycyclic aromatic hydrocarbons (PAH) containing fractions of smoked and charcoal-broiled foods, namely, Sheat fish (Kytopterus apogon), Mimrow (Crossocheilus reba), Freshwater catfish (Clarias batrachus), chicken wings, rice pork sausage and pork, in addition to naphthalene, acenaphthene, anthracene, phenanthrene, fluoranthene, pyrene, benz[a]anthracene, naphthacene, benzo[a]pyrene, benzo[e]pyrene, 9,10-dimethyl-1,2-benzanthracene, dibenz[ah]anthracene, benzo[ghi]perylene and coronene, were evaluated for their mutagenic potential using Salmonella typhimurium strains TA98 and TA100 in the absence of metabolic activation after being treated with nitrite (500 mM) for 4 hr at 37 degrees C and in acid solution pH 3.0-3.5. The presence of N-nitroso compounds was also determined. Results showed that nitrite could convert most samples to direct-acting mutagens towards both strains except for fluoranthene and benzo[ghi]perylene, which exhibit mutagenicity only with TA98. It was demonstrated that treatment of PAHs with nitrite in acid solution produced some non-N-nitroso direct-acting mutagens, suggesting that they might belong to nitro-PAHs. Therefore, the consumption of charcoal-broiled and smoked foods simultaneously with nitrite is not recommended.     

Analysis of the imidazoacridinone C1311 by high-performance liquid chromatography

Natural polyphenols found in rosemary have not only potent antioxidant activities but also anticarcinogenic properties. We have studied some of the molecular mechanisms involved in their chemopreventive action using in vitro human liver and bronchial cell models. Rosemary extract, or its active components, carnosol or carnosic acid are potent inhibitors of DNA adduct formation induced by benzo(a)pyrene or aflatoxin B1. At least two mechanisms are involved in the anticarcinogenic action of rosemary extract: (i) inhibition of the metabolic activation of procarcinogens catalysed by the phase I cytochrome P450 enzymes; (ii) induction of the detoxification pathway catalysed by the phase II enzymes such as glutathione S-transferase.     

Priorities assessment for studies of mutagen production in cooked foods

As a component of a project investigating the formation of mutagens in foods under normal cooking processes, dietary practices in the U.S. were assessed for the purpose of setting priorities for food items to be tested for possible mutagen information when cooked. High-protein foods are of primary concern because cooking of these foods results in greater mutagenic activity compared to cooking of other foods. Highest priorities were given to foods on the basis of the following criteria: (a) food items high in protein, (b) food items consumed in large amounts, and (c) food items normally cooked. Some inconsistencies in the results of two national food consumption surveys were discussed, as were the problems inherent in cooking method terminology. Emphasis was given to the need for further research in cooking practices of the U.S. population.     

Dietary nitrosodimethylamine and the risk of lung cancer: a case-control study from Uruguay

Evidence from animal studies indicates that various N-nitroso compounds are carcinogenic. We investigated whether consumption of nitrosodimethylamine (NDMA) and foods and beverages containing NDMA are carcinogenic for the lung. In a hospital-based case-control study in Uruguay, dietary intake of NDMA and its food sources was measured in 320 cases of lung cancer and 320 controls afflicted with diseases not related with tobacco use and diet. After adjusting for tobacco smoking and total energy intake, NDMA displayed a significant dose-response pattern, with a 3-fold increase in risk for the higher category of intake. The risks were slightly more elevated for adenocarcinoma of the lung. Also, salted meat consumption and beer intake were associated with an increased risk of lung cancer.     

Science among the Saguaros

This study provides a comparison among 10 patients of old and new formulas of Zilactin (Zila Pharmaceuticals, Phoenix). The original formula contained tannic acid; the new formula replaced tannic acid with benzyl alcohol as the active ingredient. The U.S Food and Drug Administration's (FDA) ruling that tannic acid must be eliminated as the active ingredient from the Zilactin formula was the reason for the change. In the study, no side effects were reported for either formula, except for a minor burning sensation at the time of application. Moreover, the new Zilactin formula, on average, provided a statistically significant rate of adherence of 21 percent to the oral mucosa.     

Specificity of chromosome damage caused by the Rex element of Drosophila melanogaster

Alkylresorcinols, natural amphiphilic compounds commonly found in cereal grains, markedly decreased mutagenic activity of four standard mutagens examined in the Ames test. The effect was the strongest in the case of indirect-acting mutagens, benzo[a]pyrene and 2-aminofluorene. In the case of direct-acting mutagens, daunorubicin and methyl methanesulfonate, the diminution of the mutagenic activity by the alkylresorcinols was smaller but still noticeable. In the Sister Chromatid Exchanges test (SCEs) with cultured in vitro human blood-derived lymphocytes, a significant decrease of SCEs frequency induced by benzo[a]pyrene was observed in the presence of alkylresorcinols. These preliminary results seem to be important in the aspect of possible antimutagenic and anticarcinogenic potency of alkylresorcinols found in cereal grains.     

In vitro reduction of virus infectivity by antibody-dependent cell-mediated immunity

Germ cell mutagens are among the most important chemicals for which chemopreventive agents should be sought and mechanistically defined. These mutagens may include environmental chemicals as well as drugs. In this investigation, the literature was reviewed for substances antimutagenic (or anticlastogenic) to compounds identified as mutagens in at least two germ cell studies. A complete matrix of test results was prepared to identify commonly tested pairs of germ cell mutagens and antimutagens. The categories of antimutagens most tested included vitamins, fatty acids, thiols, tannins and other phenolics. The most frequently studied mutagens were benzo[a]pyrene, cyclophosphamide, mitomycin C, and bleomycin. Based on the availability of the most relevant data, the analysis presented here focused on in vivo tests, specifically on bone marrow cytogenetics. The results indicated that antimutagens commonly found in the diet or endogenously in the body effectively antagonized the cytogenetic damage induced in the bone marrow by most of the germ cell mutagens studied to date. Bone marrow micronucleus and chromosomal aberration assays, which detect systemically active mutagens, may be predictive of similar mitigating effects in germ cells. Test results from antimutagenicity studies in germ cells, though limited, were comparable to the results from studies in the mouse bone marrow micronucleus test.     

Potassium, sodium, and cancer: a review

Agents known or believed to be carcinogenic decrease the concentration of potassium and increase the concentration of sodium in the cells. Anticarcinogenic agents have the opposite effect. In all cases where we have information on an agent's carcinogenicity or anticarcinogenicity and on that agent's effects on cellular potassium and sodium concentrations the above relationships have been found to be true. Dietary carcinogenic agents studied include sodium, cadmium, fat, cholesterol, calories, and alcohol; dietary anticarcinogenic agents include potassium, vitamins A, C, and D, selenium, and fiber. The effect of calcium intake is less clear as that effect depends on the concentrations on sodium and potassium. Not only dietary agents but also other carcinogenic and anticarcinogenic agents work in the same way. The cancer-causing drug dimethylhydrazine increases sodium and decreases potassium in the cells, whereas, for example, indomethacin, an anticarcinogen, has the opposite effect. In aging potassium leaves the cells, sodium enters them, and the rates of cancer increase. Patients with hyperkalemic diseases (Parkinson, Addison) have reduced cancer rates, and patients with hypokalemic diseases (alcoholism, obesity, stress) have increased cancer rates.