Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols.

The beverage tea, from the top leaves of the plant Camellia sinensis is one of the most widely used beverages in the world, second only to water. Black and green tea have mostly similar actions. The active components are polyphenols, mainly epigallocatechin gallate in green tea, and the tea leaf polyphenol oxidase mediated oxidation to oolong and black tea, yielding other polyphenols, theaflavin and thearubigins. There is 40-50 mg caffeine in a 160-ml cup of tea. The chemopreventive effects of tea depend on: (1) its action as an antioxidant; (2) the specific induction of detoxifying enzymes; (3) its molecular regulatory functions on cellular growth, development and apoptosis; and (4) a selective improvement in the function of the intestinal bacterial flora. The oxidation of LDL cholesterol, associated with a risk for atherosclerosis and heart disease, is inhibited by tea. Many of cancers are caused by lifestyle elements. One is cigarette and tobacco use, leading to cancer in the oral cavity, esophagus and lung, inhibited by tea. Mice administered a tobacco nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), developed significantly fewer lung tumors than controls when given green tea or its major polyphenol, epigallocatechin gallate (EGCG). Tea suppressed the formation of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, in the lung DNA of mice given NNK. Gastric cancer, caused by a combination of Helicobacter pylori and salted foods, is lower in tea drinkers. Western nutritionally-linked cancers of the breast, colon, prostate and pancreas can be inhibited by tea. The formation of genotoxic carcinogens for these target organs during the cooking of meats, heterocyclic amines, and their effects were decreased by tea. Tea inhibited the formation of reactive oxygen species and radicals and induced cytochromes P450 1A1, 1A2 and 2B1, and glucuronosyl transferase. The higher formation of glucuronides represents an important mechanism in detoxification. The developmental aspects and growth of cancers through promotion are decreased by tea. The regular use of a widely available, tasty, inexpensive beverage, tea, has displayed valuable preventive properties in chronic human diseases.

Induction of UDP-glucuronosyltransferase 1 (UDP-GT1) gene complex by green tea in male F344 rats.

Tea is one of the most frequently consumed beverages in the world, second only to water. Epidemiological studies have associated the consumption of green tea with a lower risk of several types of cancers, including stomach, oral cavity, esophagus, and lung. This paper deals with the mechanism of action of tea as an effective chemopreventive agent for toxic chemicals and especially carcinogens. UDP-glucuronosyltransferase (UDP-GT) activities towards p-nitrophenol were markedly increased (51.8% or 1.5-fold) in rats that consumed tea compared with the control animals on water. Induction of UDP-glucuronosyltransferase activity by tea may involve the UDP-GT1 (UGT1A) gene complex of the UDP-GT multigene family. Therefore, a major mechanism of tea as a chemopreventive agent is induction of the microsomal detoxification enzyme, UDP-glucuronosyltransferase.

Lifestyle, health and disease prevention: the underlying mechanisms.

International studies in geographic pathology provide background information that a disease may have a quite different incidence and resulting mortality as a function of area of residence. Investigations in animals can model fairly precisely what is learned through such international research, and provide the basis for examining relevant hypotheses and, more importantly, possible mechanisms of action. These approaches can yield public health recommendations and health promotion activities. Regular intake of foods rich in saturated fats, such as meat and certain dairy products, raises the risk of coronary heart disease, especially in smokers. The total mixed fat intake is associated with a higher incidence of the nutritionally linked cancers (i.e. of the postmenopausal breast, distal colon, prostate, pancreas, ovary and endometrium). Monounsaturated oils, such as olive or canola oil, are low-risk fats, as shown in animal models, and through the finding that the incidence of coronary heart and neoplastic diseases is lower in the Mediterranean region, where such oils are customarily used. Fish and fish oils are protective. The associated genotoxic carcinogens for several of these cancers, and also in heart disease causation, are heterocyclic amines, produced during the broiling and frying of creatinine-containing foods such as meats. Excessive salt intake is associated with high blood pressure and with stomach cancer, especially with inadequate intake of potassium, from fruits and vegetables, and calcium from certain vegetables and low-fat dairy products. Bran cereal fiber intake, especially with adequate calcium, yields an increased stool bulk, eliminating factors involved in colon and breast cancer. Vegetables and fruits, as well as soy products, are rich in antioxidants that are essential to lower disease risk stemming from reactive oxygen species in the body. Green and black tea are excellent sources of such beneficial antioxidants of a polyphenol nature, as are cocoa and chocolates. Antioxidants also extend healthy aging and may protect against Alzheimer's and Parkinson's diseases. Nutritional lifestyles can be described for most populations in the world and offer the possibility of a healthy long life.

Differential effects of CYP2E1 status on the metabolic activation of the colon carcinogens azoxymethane and methylazoxymethanol.

Methylazoxymethanol (MAM) and its chemical and metabolic precursor, azoxymethane (AOM), both strong colon carcinogens in rodents, can be metabolically activated by CYP2E1 in vitro. Using CYP2E1-null mice, we found that CYP2E1 deficiency differentially affects the activation of AOM and MAM, as reflected in DNA guanine alkylation in the colon and in the formation of colonic aberrant crypt foci (ACF). Male and female inbred 129/SV wild-type (WT) and CYP2E1-null (null) mice were treated with 189 micromol/kg of either AOM or methylazoxymethyl acetate (MAMAc), and 7-methylguanine (7-MeG) and O(6)-methylguanine (O(6)-MeG) were measured in the DNAs of various organs. The levels of O(6)-MeG (as pmol/nmol guanine) in the liver, colon, kidney, and lung of male null mice treated with AOM were 87, 48, 70, and 43% lower, respectively, than in AOM-treated WT mice. In null mice treated with MAMAc, the DNA O(6)-MeG levels were lower by 38% in the liver but were higher by 368, 146, and 194% in the colon, kidney, and lung, respectively, compared with the same organs of WT mice treated in the same way. Determination of ACF revealed that although AOM-induced ACF formation was significantly lower in the null group than in the WT group, MAMAc-induced ACF formation was significantly higher in the null group than in the WT group. These results demonstrate an important role for CYP2E1 in the in vivo activation of AOM and MAM and suggest that agents that modify CYP2E1 activity at the tumor initiation stage might either enhance or inhibit colon carcinogenesis, depending on whether AOM or MAMAc is used as the carcinogen. The mechanism of this effect is discussed.

Chemopreventive effects of cocoa polyphenols on chronic diseases.

We have explored the causes of the major chronic diseases prevailing in the world and the relevant mechanisms as a sound basis for recommendations for their prevention. Research shows that the cocoa bean, and tasty products derived from the cocoa bean such as chocolate, and the beverage cocoa, popular with many people worldwide, is rich in specific antioxidants, with the basic structure of catechins and epicatechin, and especially the polymers procyanidins, polyphenols similar to those found in vegetables and tea. Metabolic epidemiological studies indicate that regular intake of such products increases the plasma level of antioxidants, a desirable attribute as a defense against reactive oxygen species (ROS). The antioxidants in cocoa can prevent the oxidation of LDL-cholesterol, related to the mechanism of protection in heart disease. Likewise, a few studies show that ROS associated with the carcinogenic processes is also inhibited, although there have not been many studies on a possible lower risk of various types of cancer either in humans or in animal models consuming cocoa butter or chocolates. Based on the knowledge acquired thus far, it would seem reasonable to suggest inhibition of the several phases of the complex processes leading to cancer, as a function of quantitative intake of antioxidants, including those from cocoa and chocolates. Cocoa and chocolate also contain fats from cocoa butter. These are mainly stearic triglycerides (C18:0) that are less well absorbed than other fats, and are excreted in the feces. Thus, cocoa butter is less bioavailable and has minimal effect on serum cholesterol.

Antimutagenesis and anticarcinogenesis, from the past to the future.

Observations on cancer causation are some 150 years old, but actual detailed research on elements bearing on cancer started at the beginning of the twentieth century. Rapid progress, however, is only some 40 years old. Studies in humans documented certain lifestyle related factors to lead to cancer, and research in animal models strengthened this information. With the realization that there are carcinogens that in a metabolically activated attack DNA, in contrast to other agents that act by promoting, enhancing processes through totally distinct mechanisms, it became possible to develop and apply tests for DNA reactivity, in a prokaryotic organism, the widely used Salmonella typhimurium test by Ames and in a eukaryotic system, namely freshly explanted liver cells displaying evidence of DNA repair by Williams. A battery of these two tests are over 90% accurate in defining genotoxicity. Virtually all documented human carcinogens are genotoxic. With advances in molecular biology, mutational events are traced to changes in tumor suppressor genes or in oncogenes, that can serve as markers of risk. In addition, reactive oxygen systems (ROS) are involved in both the early steps in cancer and in the developmental aspects. Thus, foods containing antioxidants such as vegetables, fruits, soy products, cocoa and tea that counteract ROS are protective in cancer causation and development. Worldwide application of current knowledge and mechanisms to cancer prevention, the definitive means of cancer control, is likely to lower not only cancer but also heart disease risk in the current century.

Urinary excretion of N-OH-2-amino-3-methylimidazo[4,5-f]quinoline-N-glucuronide in F344 rats is enhanced by green tea.

The effects of green tea on the metabolism of the food carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) with emphasis on the formation of the detoxified glucuronides was studied. Two groups of 20 adult male and female Fischer 344 rats consumed 2% green tea or water for 6 weeks before being administered a single dose of 40 mg/kg body weight of [2-14C]IQ by oral gavage. Major metabolites in 24 h urine samples were separated by high-performance liquid chromatography (HPLC), including N-OH-IQ-N-glucuronide, 5-OH-IQ glucuronide and sulfate, IQ sulfamate and IQ itself. The structures of the main metabolites were established by mobility on the HPLC and by mass spectrometry. Sulfate esters and sulfamate were hydrolyzed by 0.1 N HCl for 15 min at 100 degrees C, yielding 5-OH-IQ and high levels of IQ. HPLC of the resulting product showed the N-OH-IQ-N-glucuronide and the 5-OH-IQ glucuronide, as well as IQ. The male and female rats drinking tea displayed a significantly higher (P < 0.05) excretion of the two major glucuronides. We conclude that intake of green tea increases the excretion of N-OH-IQ-N-glucuronide, a detoxified metabolite of the proximate carcinogen N-OH-IQ.

Investigation of commercial Mitolife as an antioxidant and antimutagen.

Coronary heart disease and many types of cancer are important diseases in the world and especially in Western countries. There are biochemical activation processes for low-density lipoprotein cholesterol and genotoxic carcinogens to reactive products. In part, these also involve the generation of active oxygen and reactive oxygen species. We investigated the effect of a natural product, MitoLife, which contains a mixture of fruit and tea extracts, on the oxidation of low-density lipoprotein cholesterol and the mutagenicity of five genotoxic carcinogens, specifically, 2-acetylaminofluorene, 2-aminoanthracene, 2-amino-3-methylimidazo[4,5-f]quinoline, aflatoxin B(1), and benzo[a]pyrene. A positive antioxidant control, polyphenon 60, a concentrate of green-tea polyphenols, was used to compare the effect of MitoLife with that of polyphenon. MitoLife displayed inhibiting effects in all series of tests at slightly lower effectiveness but with the same order of magnitude as the green-tea polyphenol product. Thus, MitoLife represents another means to decrease adverse effects associated with the oxidation of low-density lipoprotein cholesterol or of a series of carcinogens, some of which are in the human environment.

Green tea and the metabolism of 2-amino-3-methylimidazo.

The effects of green tea intake on the metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in the rat was studied. IQ belongs to a new class of mutagens and carcinogens, heterocyclic arylamines, formed during cooking through browning meats and fish, thus, in the food chain of most non-vegetarians. Ten adult male and female Fischer 344 rats were placed on a 2% solution of green tea and 10 control rats were on water for 6 weeks. Then, animals were administered a single dose of 40 mg/kg body weight of [2-14C]IQ by oral gavage. Twenty-four hour urine samples were collected and metabolites were separated by HPLC and quantitated by scintillation counting. Two minor and three major metabolites were isolated, including, small quantities of IQ itself. The rats on tea showed significant differences (P < 0.05) in the recovery of the three major metabolites, namely, IQ-sulfamate, IQ-5-O-sulfate, and IQ-5-O-glucuronide, respectively. Green tea, therefore, influences the manner in which the food carcinogen IQ is metabolized and excreted in urine. Formation of glucuronides, increased by green tea, represent a key means of detoxification of the heterocyclic amine, IQ.

Eat to live, not live to eat.

Most of the prevailing chronic diseases in the world have an important nutritional component by directly causing a specific disease, enhancing the risk through phenomena of promotion, exerting a beneficial effect in decreasing risk, or preventing the disease. International studies in geographic pathology have shown that a given disease may have vastly different incidence and mortality as a function of residence. Laboratory research in animal models can reproduce fairly accurately what is learned through international research and provide the basis for examining relevant hypotheses and, more importantly, proposed mechanisms of action. Validation of these approaches can be the basis for public-health recommendations and health-promotion activities. Through such techniques, it has been found that regular intake of foods with saturated fats such as meat and certain dairy products raise the risk of coronary heart disease. The total mixed-fat intake is associated with a higher incidence of the nutritionally linked cancers, specifically cancer of the postmenopausal breast, distal colon, prostate, pancreas. ovary, and endometrium. The associated genotoxic carcinogens for several of these cancers are heterocyclic amines, which also play a role in heart-disease causation, and these are produced during the broiling and frying of creatinine-containing foods such as meats. Monounsaturated oils such as olive or canola oil are low-risk fats as shown in animal models and through the observation that the incidence of specific diseases is lower in the Mediterranean region, where such oils are customarily used. High salt intake is associated with high blood pressure and with stomach cancer, especially with inadequate intake of potassium from fruits and vegetables and of calcium from certain vegetables and low-fat dairy products. Vegetables, fruits, and soy products are rich in antioxidants that are essential to lower disease risk stemming from reactive oxygen systems in the body. Green and black teas are excellent sources of antioxidants of a polyphenol nature. as is cocoa and some chocolates. Nutritional lifestyles that offer the possibility of a healthy long life can be adopted by most populations in the world.

Approaches for chronic disease prevention based on current understanding of underlying mechanisms.

Much progress has been achieved by exploring the causes of the main human cancers and of cardiovascular and cerebrovascular diseases. Even more important has been the knowledge acquired about the mechanisms underlying the development of these diseases. In many parts of the world, particularly in the West, the major cancers associated with dietary habits involve the postmenopausal breast, distal colon, prostate, pancreas, ovary, and endometrium. Current evidence suggests that the genotoxic carcinogens for all but the last 2 of these diseases stem from the traditional intake of fried and broiled foods such as meats. The surface of these foods contains a class of powerful mutagens, heterocyclic amines, which are carcinogenic to the target organs in animal models. Fish-eating populations have lower incidences of heart disease and of many types of cancers than do other populations, which may be the result of the n-3 polyunsaturated oils found in fish. Among other dietary practices that may reduce the risk of cancer and cardiovascular disease are consuming 5-9 servings of fruits and vegetables daily, which provides antioxidants such as quercetin and isothiocyanates; having a high fiber intake, including bran cereal; and drinking 1.5-2.5 L of fluids daily. Tea polyphenols found in black and green tea may have a protective effect against heart disease and some cancers. Concentrates of such desirable products have been made available in pill form to complement health-promoting personal lifestyles. Biomedical research funded by The National Institutes of Health and organizations such as the American Cancer Society has produced sound results that could lead to prevention of chronic disease. The public must heed this information to achieve long-term health.

Prevention of cancer and other chronic diseases worldwide based on sound mechanisms.

The transformation of normal cells by DNA reactive, genotoxic carcinogens and the growth promotion and development of mutated cells by enhancing factors is involved in the overall basic mechanism of cancer induction. Thus, discrimination between genotoxic carcinogens and nongenotoxic chemicals is essential. The dose-response curves, reversibility, and organ-and species specificity are distinct. Genotoxic carcinogens are mutagenic, form DNA adducts, induce DNA repair, and form hydroxy radicals and inappropriate peroxidation reactions that antioxidants such as those in vegetables, fruits, and tea can decrease. In contrast, promoters do not form DNA adducts, but raise cell duplication rates, among other attributes. In the USA, about 35% of known cancers are associated with tobacco use and about 55% with inappropriate nutritional habits. Cancer induction can be decreased by avoiding the formation of carcinogens, reducing their metabolic activation, or increasing their detoxification. Excessive dietary salt, and heterocyclic arylamines formed in cooking of meats or fish, and high intake of 40% of calories in fats are health risks, but vegetables, fruits, tea, soy products, and fibers are protective. We review nutritional factors involved in cancer and chronic disease causation and prevention.

Carcinogenicity and mutagenicity testing, then and now.

Cancer is a dread disease worldwide. Mortality of individuals suffering from cancer is high, despite the current improved methods of precocious detection, surgery and therapy. Prevention of cancer is the recognized goal of many activities in cancer research. This aim was recognized early to involve the bioassay of environmental chemicals or mixtures. The first such study involved application of coal tar to the ear of rabbits, and later on to the skin of mice. Subsequently, laboratory rats were introduced, and hamsters were utilized as a substitute for the unwieldy tests in rabbits. Investigators also became concerned with the mechanisms of carcinogenesis, and more definitive approaches to carcinogen bioassay in laboratory animals, as possible indicators of cancer risk in humans. These tests were expensive and lengthy, and did not serve the important purpose of accurately measuring risk of cancer to humans. Once it was realized that DNA and the genetic apparatus might be a key target, rapid bioassays in bacterial and mammalian cell systems were introduced successfully. Thus, batteries of tests are now available to detect effectively human cancer risks, and provide novel approaches to determine the underlying mechanisms, as a sound basis for cancer prevention.

Mechanisms of action of antioxidants as exemplified in vegetables, tomatoes and tea.

Most chronic diseases, including coronary heart disease and many types of cancer depend on the in vivo conversion of cellular macromolecules or of carcinogens to specific reactive, oxidized forms. For that reason, health promoting nutrition involves the daily intake of five to 10 vegetables and fruits, fruit juices, red wine and tea that are rich sources of micronutrients with antioxidant properties, including the antioxidant vitamins C, E and beta-carotene. Tomatoes contain lycopene, a stable, active antioxidant. Many vegetables contain quercetin and related polyphenolic compounds. Tea is a source of epigallocatechin gallate, in green tea, and theaflavin and the associated thearubigins, in black tea. Red wine contains resveratrol. The diverse antioxidants in foods, red wine and tea provide the necessary antioxidant resources for the body to control oxidation reactions in the body with possible adverse consequences. For example, the oxidation of low density lipoprotein (LDL) cholesterol yields a product that damages the vascular system. Thus, a lower intake of saturated fats to decrease the levels of LDL cholesterol, together with an adequate intake of antioxidants, is the optimal approach to lower heart disease risk. Cancer of the stomach involves the consumption of salted, pickled foods yielding direct-acting carcinogens, and their formation is inhibited by vitamins C and E. Cancer in the colon, breast, prostate and pancreas may be caused by a new class of carcinogens, the heterocyclic amines, formed during the broiling or frying of creatinine-containing foods, including fish and meats. Their formation and action can be inhibited by antioxidants such as those in soy, tea, vitamin C and also by the synthetic antioxidants BHA or BHT. The growth, cell proliferation and development of abnormal preneoplastic and neoplastic cells also involves oxidation reactions, including the formation of active oxygen or peroxy compounds. Such reactions can be inhibited by antioxidants, such as those in tea, tomatoes or vegetables. Even ageing and longevity in good health would be favoured by the availability of adequate amounts of varied antioxidants. Prevention of the formation and of action of reactive products by antioxidants as present in fruits, vegetables, tomatoes, red wine and tea is of great public health importance in decreasing the risk of major diseases. Prevention is the optimal approach to disease control, and also as an effective route to lower costs of medical care.