A perspective on the history and significance of carcinogenic and mutagenic N-substituted aryl compounds in human health.
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Carcinogens↗
Biomedical subjects
J H Weisburger
Publications and source records attributed to J H Weisburger.
Tea and health: a historical perspective.
In many parts of the world, green tea and black tea are produced from the plant Camellia sinensis. Tea is one of the most widely consumed beverages, second only to water. It is one of the safest beverages since it is made with boiling, sterile water and has been popular for over 4000 years. Dogma has it that people knew it might have health promoting properties since it was frequently used as fluid supply for patients suffering from infectious diseases. However, detailed, focused research on the health benefits of tea is of recent vintage. Initially, such research was carried out in Japan and China and, because the local customs, this research involved green tea. Now, a number of other scientists in Europe and in the United States have conducted investigations on black tea, and in some laboratories exacting comparative studies were performed utilizing black and green tea. The major interest in tea and health stems from the high level of antioxidant tea polyphenols in green tea and black tea. The chemistry of the tea polyphenols has been worked out to some extent. Thus, their role in lowering the risk of heart disease and of a number of types of cancer begins to be understood. Most productive are multi-disciplinary approaches, considering data from epidemiology and field studies, and laboratory research in animal models for heart disease and cancers of various types, as well as through in vitro experiments.
Cardiovascular Diseases↗
Tea, or tea and milk, inhibit mammary gland and colon carcinogenesis in rats.
Research was performed on the effect of tea, or tea and milk, instead of drinking water, in rat models of cancer in the mammary gland or colon. Solutions of 1.25% (w/v) black tea, or 1.85% (v/v) milk in tea were prepared three times per week. SD rats were given tea beginning at 42 days of age; one group was gavaged 5 mg 7,12-dimethylbenz[a]anthracene (DMBA) at 49 days of age; another group received 8.4 mg 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) twice per week beginning at age 49, then 14 mg twice a week for 4 weeks more. The groups on DMBA were killed 33 weeks later, and those on IQ 39 weeks later. Tea decreased the mammary gland tumor multiplicity and volume, and milk and tea had a greater protective action. Male F344 rats were given two doses of 15 mg/kg azoxymethane (AOM) on weeks 6 and 7, and some groups started on tea, or tea and milk at 5 weeks; one group started on tea 2 days after AOM. Foci of aberrant crypts in the colon were decreased, after 9 weeks, in the groups on tea, or tea and milk during AOM administration, but not after AOM. Thus, tea decreases mammary tumor induction, and the production of foci of aberrant crypts in the colon. Milk potentiates these inhibiting effects.
9,10-Dimethyl-1,2-benzanthracene↗
Inhibition of PhIP mutagenicity by catechins, and by theaflavins and gallate esters.
Aqueous solutions of gallic acid, methyl gallate, catechins, theaflavins and tannic acid were tested for inhibition of the mutagenicity of PhIP in the Salmonella typhimurium TA98 assay with an S9 fraction from the liver of rats induced with alpha-naphthoflavone and phenobarbital. The IC50S were in the 80-250 microM range for the gallated catechins, theaflavins and tannic acid. No inhibition could be found with these compounds when a direct acting mutagen was used. This indicates that the anti-mutagenic properties of these phenolic compounds may be due to their inhibition of the cytochrome P-450 enzymes.
Animals↗
Dietary fat and risk of chronic disease: mechanistic insights from experimental studies.
The primary nutritionally linked diseases are coronary heart disease, stroke and cancers of the stomach, colon, pancreas, prostate, breast, ovary, and endometrium. Dietary fats operate through a promoting mechanism. An S-shaped dose-response curve with a threshold has been demonstrated in models of breast and colon cancer in which the standard Western fat intake of 40% of energy yields a high level of promotion, and reduction of fat to 10% to 20% of energy (the traditional Japanese fat intake) has a low promoting action. In models of breast and colon cancer, saturated fats such as beef fat or lard, and monounsaturated oils, such as olive oil, display only a weak promoting effect, with the incidence of induced tumors being similar at intake levels of 40% and 10% of energy. On the other hand, the n-6-polyunsaturated oils display a strong promoting effect. Such findings may have a parallel in the low but definitely increasing slope of postmenopausal breast cancer incidence in the past 30 years as the American public decreased saturated fat intake to avoid heart disease and increased use of the n-6-polyunsaturated oils. Mechanisms underlying the cancer-promoting effect in the colon stem from increased hepatic production of bile acids, which are transferred to the intestinal tract via the bile. Ingestion of 40% fat calories yields higher concentrations of bile acids in the colon than lower levels of dietary fat ingestion. Cancer in the mammary gland is promoted through higher concentrations of fats and phospholipids in the gland as well as increased levels of estrogen secondary to production by the ovary and other endocrine tissues that, in turn, affect the generation of pituitary hormones such as prolactin and growth hormone. The n-3-fats, as found in fish and fish oils, have a pronounced inhibitory effect in models of colon and breast cancer, presumably through their shifting of prostaglandin metabolism to the generation of prostaglandins, which lower cell proliferation potential and, thus, decrease promotional effects. The role of dietary fat as a promoter can be modified by other nutritional components. Finally, one of the best pieces of evidence for an enhancing effect of many dietary fats in the nutritionally linked cancers is the current increase in the incidence of these diseases in Japan as the nutritional habits of people in that country become more Westernized.
Animals↗
Comments on Swiss plan to fight against breast cancer, International Cancer News, Eur J Cancer, 32A, no. 11, pp. 1830-1831, 1996.
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Breast Neoplasms↗
International symposium on the role of lycopene and tomato products in disease prevention.
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Anticarcinogenic Agents↗
Effect of 2-chloro-4-methylthiobutanoic acid in a rapid bioassay for gastric carcinogens.
2-Chloro-4-methylthiobutanoic acid (CMBA, a mutagen from Japanese salted fish) at 15-500 mg/kg body weight induced several-fold increase in replicative DNA synthesis (RDS) (P < 0.05) after 80 min and 17 h, equivocal unscheduled DNA synthesis (UDS) after 80 min and necrosis 80 min after its administration in the stomach pyloric mucosa of F344 and ACI male rats. A positive control, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 50 mg/kg body weight), induced RDS, UDS and erosion. However, the negative control L-methionine (500 mg/kg body weight) did not display any effect. The results suggest possible tumor-initiating and -promoting activity of CMBA but at a lower potency than that of MNNG.
Animals↗
Tea polyphenols as inhibitors of mutagenicity of major classes of carcinogens.
Previous research suggested that the mutagenicity of some genotoxic carcinogens, mainly heterocyclic amines, was decreased by green or black tea extracts, or tea polyphenol fractions. Thus, it seemed important to test a variety of genotoxic carcinogens with distinct chemical structures and means of biochemical activation as regards modification of mutagenicity in appropriate strains of Salmonella typhimurium by 3 concentrations of polyphenols 60, 100, or B, standard commercial polyphenol preparations from green or black tea. Polyphenols sharply decreased the mutagenicity of a number of aryl- and heterocyclic amines, of aflatoxin B1, benzo[a]pyrene, 1,2-dibromoethane, and more selectively, of 2-nitropropane, all involving an induced rat liver S9 fraction. Good inhibition was found with 2 nitrosamines that required a hamster S9 fraction for biochemical activation. No effect was found with 1-nitropyrene, and with the direct-acting (no S9) 2-chloro-4-methyl-thiobutanoic acid. Thus, with some exceptions, polyphenols considerably decreased the mutagenicity of diverse types of carcinogens.
Amines↗
Inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) mutagenicity by black and green tea extracts and polyphenols.
Solutions of lyophilized preparations of standard black and green tea extracts were made and tested over a range of six concentrations as inhibitors of the mutagenicity caused by the fool mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the Salmonella typhimurium TA98 assay containing S9 fraction from rats induced with alpha-naphthoflavone and phenobarbital. Extracts of both black and green tea were equally good inhibitors of mutagenicity. Purified polyphenols were prepared from tea extracts by solvent extraction. The polyphenols of black tea were more potent inhibitors of mutagenicity than the polyphenols of green tea. These findings suggest that black tea may have similar health-promoting properties to those reported previously for green tea.
Animals↗
Microsatellite instability and loss of heterozygosity on chromosome 10 in rat mammary tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
Microsatellite instability (MI) and loss of heterozygosity (LOH) were examined in mammary tumors induced in Sprague-Dawley x F344 F1 female rats by 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Examination of 62 microsatellite loci revealed MI in nine of 15 (60%) PhIP-induced mammary tumors, and five of these MI-positive tumors had mutations in more than one microsatellite locus. In contrast, two of 12 (17%) 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors were MI positive but had mutations at only one locus each. Further, by using 37 polymorphic markers specific LOH was observed in four of 15 PhIP induced mammary tumors on distal parts of rat chromosome 10, which is homologous to human chromosome 17q with no background level of LOH. Similarly, DMBA-induced mammary tumors showed specific LOH on the same region of chromosome 10. These data suggest that mismatch-repair deficiency and loss of chromosome 10 are involved in carcinogenesis of PhIP-induced rat mammary tumors.
Animals↗
Chemical carcinogen mechanisms of action and implications for testing methodology.
Chemical carcinogens are of two distinct types, DNA-reactive and epigenetic. Testing methodology can be directed toward detecting effects of both types of carcinogen. Carcinogens of the DNA-reactive type are defined by the formation of covalently bound DNA adducts. These chemicals have structures that yield electrophilic reactants either directly or after bioactivation. These agents cause genomic alteration in the structure or function of DNA in the target cell. In addition, these compounds can exert other cellular and tissue epigenetic effects, such as cell proliferation and growth promotion. Carcinogens of the epigenetic (paragenetic) type, in contrast, do not react with DNA, but rather display cellular effects such as neoplasm growth promotion, cytotoxicity, inhibition of tissue growth regulation, peroxisome proliferation, endocrine modification, immunosuppression and/or sustained tissue ischemia that can be the basis for increases in neoplasia. Their chemical structure is such that they do not give rise to a reactive electrophile. The testing methodologies to identify either type follow a Decision Point Approach designed to identify potential carcinogenicity and yield mechanistic information on the production of effects that underlie carcinogenicity. It has 5 stages focusing on the chemical structure, DNA-reactivity, epigenetic effects, limited bioassays and finally the application of the accelerated bioassay (ABA). ABA requires 40 weeks and applies the use of sensitive markers for induction of neoplasia in comparison to positive control compounds for important organs in human carcinogenesis. It enables data acquisition of the entire carcinogenic process directed toward developing mechanistic information. The ABA has the potential to replace the chronic bioassay in rodents in some circumstances and can serve as an alternative to a chronic bioassay in a second species.
Animals↗
The 37 year history of the Delaney Clause.
The Delaney Clause has been part of the US Food, Drug and Cosmetic laws since it was enacted by the Congress in 1958. It states that no cancer-causing agent, as demonstrated in humans or animals, shall be deliberately added to, or found as a contaminant in food. The FDA was charged with enforcing this Clause. Other agencies such as EPA used similar approaches with the avowed aim to prevent cancer. Legal cases have been brought against Agencies who failed to comply with this law to the letter. Since 1958, research has elucidated the main mechanisms whereby chemicals cause cancer. The leading causative factors of the major human cancers are basically known, and include smoking and tobacco use, excessive alcohol, and common dietary practices and nutritional traditions. The etiology of lymphomas, leukemias and cervical cancer may be viruses. The Delaney Clause was designed to protect against these many cancer types. It was based on the hypothesis held in the 1950s that human cancers are due to environmental chemicals. This is clearly not true for the great majority of cancers and therefore, the Delaney Clause as framed has not saved any lives, is obsolete, and should be eliminated.
Animals↗
Human protection against non-genotoxic carcinogens in the US without the Delaney Clause.
Cancers of many types are major chronic diseases with a high fatality rate and a high cost to society. In the USA, the Delaney Clause was implemented in 1958 because the public believed that many cancers stem from food additives and food contaminants. In the intervening years, research has provided key information about the mechanisms of carcinogenesis and demonstrated that there are two major classes of carcinogens, genotoxic and non-genotoxic. Two case reports are presented, of sodium saccharin and ethylenebisdithiocarbamates that were banned based on the Delaney Clause in an unjustified manner, based on the underlying mechanisms not relevant for non-genotoxic carcinogens. Also, the causes of major cancers have been discovered. Most cancers are associated with lifestyle, specifically tobacco and excessive alcohol use, inappropriate nutritional traditions, and lack of exercise. These lifestyle components involve now known genotoxic carcinogens and importantly, non-genotoxic carcinogens. The effect of non-genotoxic carcinogens is highly dose dependent and also reversible upon lowering the dose below a threshold. Thus, it is quite possible to lower human cancer risk, and also the risk of related chronic diseases such as coronary heart disease, hypertension and stroke, adult on-set diabetes, by proper lifestyle adjustments. Clearly, the Delaney Clause plays no role in disease prevention.
Carcinogenicity Tests↗
Risk assessment of carcinogens in food with special consideration of non-genotoxic carcinogens. Scientific arguments for use of risk assessment and for changing the Delaney Clause specifically.
The document "Risk Assessment of Carcinogens in Food with Special Consideration of Non-Genotoxic Carcinogens" was produced by the International Federation of Societies of Toxicologic Pathologists on the occasion of its triannual meeting in Tours, France, April 23-26, 1995. Subsequently, it was endorsed by the North American Society of Toxicologic Pathologists at its annual meeting in San Diego, CA, USA, June 11-15, 1995. This document was written to address up-to-date risk assessment of carcinogens and anachronisms in the Delaney Clause of the US Federal Food, Drug and Cosmetic Act which have become evident since its enactment in 1958. In the intervening years, major progress has been made in understanding mechanisms of cancer induction and in recognizing causes of human cancer. The Clause in conjunction with its present legal interpretation and implementation does not provide for rational, scientific evaluation of carcinogens. It ignores the fact that the diverse mechanisms now known to underlie cancer increases in rodents exposed to high doses of chemicals are often inapplicable to man. In this regard, current evaluation of chemicals based on the tenets of the Delaney Clause is irrational in many cases. The document presents several examples of chemicals to which humans may be exposed through food and which illustrate the need for science-based risk assessment. Appropriate risk assessment methods are available to provide assurance of negligible risk, and accordingly, it is recommended that the Delaney Clause be rescinded as it has outlived its usefulness. This will enable US governmental agencies to regulate the use of chemicals in foods by using appropriate current scientific methods on a case by case basis within the context of other relevant legislation.
Animals↗
Specific 5'-GGGA-3'-->5'-GGA-3' mutation of the Apc gene in rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
The APC gene plays a major role in human colon carcinogenesis. We determined the genomic structure of the rat Apc gene, and we analyzed mutations in colon tumors induced in F344 rats by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), potent carcinogens contained in ordinary daily human food. Of eight PhIP-induced tumors, one tumor had two Apc mutations, two tumors had a mutation with loss of the normal allele, and one had a mutation. Two of the above five mutations were at nucleotide 1903, one at 2605, and two at 4237, all being a deletion of a guanine base at the 5'-GGGA-3' site and resulting in truncation of the APC protein. Of 13 IQ-induced tumors, 2 had an Apc mutation with loss of the normal allele. The two mutations were a missense mutation (T-->C) at nucleotide 1567 and a nonsense mutation (C-->T) at 2761. Alteration of the Apc gene was shown to play a more important role in PhIP-induced than in IQ-induced rat colon carcinogenesis. PhIP-induced tumors are characterized by their specific and unique mutation, which may be useful for mutational fingerprinting of human cancers.
Animals↗
Screening of tea clones for inhibition of PhIP mutagenicity.
Standard black and green tea extracts have been known to inhibit mutagenicity caused by PhIP, in the Salmonella typhimurium TA98 assay containing S9 fraction from the liver of rats induced with alpha-naphthoflavone and phenobarbital. Breeding and selection programs for high yielding tea clones have successfully increased yields in many tea producing areas. Six clonal teas and three seedling teas were obtained from a tea producing area in Southern Africa. Standard black and green teas were used as controls. Dose-dependent inhibition of the bacterial mutagenicity elicited by two concentrations of PhIP was found in the extracts of all the teas tested. This indicates that the clonal teas have not lost their anti-mutagenic properties. Small differences were found amongst the clonal teas in their ability to inhibit mutagenicity. This indicates that it may be possible to enhance this trait in future breeding and selection programs.
Anticarcinogenic Agents↗