A hypothesis for dietary components as blocking agents of chemical carcinogenesis: plant phenolics and pyrrole pigments.

Initiation of chemical carcinogenesis involves the intracellular formation of a highly reactive electrophile that can attack many chemical nucleophiles in the cell, including DNA, a process that seems to be a central mechanism of initiation. Competing chemical nucleophiles in the cell, such as endogenous glutathione, can act as protecting or blocking agents against the attack on DNA. There are chemical substances in our food supply that may act as anticarcinogens or antimutagens by blocking or trapping ultimate carcinogen electrophiles in a nucleophilic chemical reaction, to form innocuous products. A continuous input of these substances could serve as an additional buffer against DNA damage, supplementing the endogenous systems qualitatively and quantitatively. Certain plant phenolics can be effective inhibitors of chemical mutagens and (or) carcinogens. Tetrapyrroles and porphyrins, both plant and animal, can also act as blocking agents. Both plant phenolics and porphyrins are primarily active against aromatic carcinogens as inhibitors of mutagenesis in in vitro systems. Plant phenolics have also demonstrated inhibiting activity against aromatic chemically induced carcinogenesis.

Monsonia burkeana, widely used as ‘special tea’, is harvested unsustainably due to insufficient information on the accumulative abilities of its organs on the secondary metabolites. Using phenolics and antioxidants as focus chemical compounds, an investigation was carried out to (1) determine the accumulative abilities of organs of M. burkeana on phenolic and antioxidant compounds, and (2) determine whether phenolic acids and antioxidants in M. burkeana had density-dependent relationship patterns. Ten plants per plot, with three replicates, were harvested whole, oven-dried, separated into the four organs and quantified for phenolics and antioxidant components using the Folin Ciocalteau method and the Trolox Equivalent Antioxidant Capacity (TEAC) assay, respectively. Generally, reproductive and vegetative organs had high levels of phenolic and antioxidant compounds when compared to roots. The saturation factor suggested that more than 90% antioxidants were derivatives of the phenolic compounds. Optimum levels of antioxidant activity were attained at 5.39, 5.49, 4.36 and 4.13 mg/ 100 g of phenolics in fruit, leaf, stem and root, respectively. In conclusion, vegetative and reproductive organs are good sources of phenolic and antioxidant compounds inM. burkeana. Key words: Phenolic, antioxidant, saturation factor, optimum.

Betel-nut (BN) chewing related oral mucosal lesions are potential hazards to a large population worldwide. Genotoxicity of betel alkaloids, polyphenol and tannin fractions have been reported. It has been shown earlier that BN ingredients altered the level of endogenous glutathione (GSH) which could modulate the host susceptibility to the action of other chemical carcinogens. The north-east Indian variety of BN, locally known as 'kwai', is raw, wet and consumed unprocessed with betel-leaf and slaked lime and contains higher alkaloids, polyphenol and tannins as compared to the dried one. Therefore, the purpose of this study was to investigate the extent of DNA damage, pattern of cell kinetics, the level of p53-protein and endogenous GSH in kwai chewers in the tribal population of Meghalaya state in the northeastern region of India with an aim to see whether these end-points could serve as biomarkers of genetic damage of relevance for genotoxic/carcinogenic process. The present data show higher DNA damage, delay in cell kinetics, p53 expression and lower GSH-level in heavy chewers (HC) than nonchewers (NC). The influence of bleomycin (BLM) on chromatid break induction in G2-phase of peripheral blood lymphocytes in NC and HC has been analysed to determine individual susceptibility to carcinogenic assaults. HC showed higher induction of chromatid breaks than NC. Risk assessment in this study suggests an interaction between carcinogen exposure and mutagen sensitivity measures, risk estimates being higher in those individuals who both consume kwai and express sensitivity to free radical oxygen damage in vitro. From this study it seems that besides cytogenetical parameters, the level of endogenous GSH and the level of p53 protein could act as effective biomarkers for kwai chewers.

Simple phenol and phenolic compounds occur in a vast portion of our diet. This review attempts to discuss their occurrences relative to our food supply. In addition, their chemical, nutritional, and sensory properties are explored, as well as methods for their isolation, identification, and quantitation.

Agri-food wastes (AFW) and by-products chain still have the potential to be reprocessed into other production systems. AFW and by-products may contain components that could be valorised for their bioactivity, such as polyphenols and antioxidant molecules that can be used as a source of functional ingredients for feed industries. However the bioaccessibility of these products are higly variable and dependent on a range of factors, one of the most important being food matrix characteristic. The aim of this study was to determine the total phenolic content and the antioxidant capacity of several AFW (fruit and vegetable waste (FVW), citrus pulp, strawberry and orange dried) and by-products (grape marc, Camilina sativa cake, olive pomace and whey) using different extraction protocols. A total of 24 samples were processed using two different extraction methods: chemical extraction and in vitro physiological extraction. Afterwards, the polyphenolic content was assessed by Folin–Ciocalteu assay while antioxidant capacity was determined by 2, 2-Azino-bis-3 ethylbenzothiazoline-6-sulfonic Acid (ABTS) assay. Soy and wheat samples were included as controls in all the experiments. Results obtained showed that the chemical extracts of by-products and AFW contain different amount of polyphenols; in particular, as expected, the grape marc showed the highest polyphenolic content with a value of 4.5% w/w, followed by Camilina sativa cake, olive pomace, FVW, orange and strawberry dried showed a polyphenolic content of 1.3, 0.7, 1.3, 1.6 and 1.3 %w/w, respectively. Considering the antioxidant capacity, grape marc exhibited a significant (P<0.05) value of 573.6 μmol Trolox equivalent/g after chemical extraction compared to the other samples considered. The physiological extraction yielded high polyphenolic content and antioxidant capacity, suggesting that during the digestion the bioaccessibility of phenolic and antioxidant compounds was improved. The results obtained in this study indicate that AFW and by-products could be considered a promising source of antioxidants and phenolic compounds.

The American Association for Cancer Research has been the citadel for communicating research on chemical carcinogens for over a century. It therefore seems appropriate that a review of chemical carcinogenesis inaugurates a series of articles highlighting advances in understanding, treating, and preventing cancer.At the dawn of the 20th century, we had recognized that chemicals cause cancer, but we had not yet identified individual cancer-causing molecules, nor did we know their cellular targets. We clearly understood that carcinogenesis, at the cellular level, was predominantly an irreversible process. What we lacked was knowledge of the mechanisms by which chemicals cause cancer and the molecular changes that characterize tumor progression.We now are early in a century in which cancer is being investigated at the molecular level, and we have developed technologies that afford unprecedented power to delineate and manipulate altered pathways in cancer cells. Can we harness new insights and technologies to prevent or obliterate human cancers or delay their progression? Can we identify individuals who have a particularly high susceptibility to specific environmental carcinogens?The history of chemical carcinogenesis is punctuated by key epidemiologic observations and animal experiments that identified cancer-causing chemicals and that led to increasingly insightful experiments to establish molecular mechanisms and to reduction of human exposure. In 1914, Boveri (1) made key observations of chromosomal changes, including aneuploidy. His analysis of mitosis in frog cells and his extrapolation to human cancer is an early example of a basic research finding generating an important hypothesis (the somatic mutation hypothesis). The first experimental induction of cancer in rabbits exposed to coal tar was performed in Japan by Yamagiwa and Ichikawa (2) and was a confirmation of Pott's epidemiologic observation of scrotal cancer in chimney sweeps in the previous century (Fig. 1; ref. 3). Because coal tar is a complex mixture of chemicals, a search for specific chemical carcinogens was undertaken. British chemists, including Kennaway (4), took on this challenge and identified polycyclic aromatic hydrocarbons, for example, benzopryene, which was shown to be carcinogenic in mouse skin by Cook, Hewett, and Hieger in 1933 (5). The fact that benzopyrene and many other carcinogens were polyaromatic hydrocarbons lead the Millers (6) to postulate and verify that many chemical carcinogens required activation to electrophiles to form covalent adducts with cellular macromolecules. This in turn prompted Conney and the Millers (7) to identify microsomal enzymes (P450s) that activated many drugs and chemical carcinogens.The discovery of DNA as the genetic material by Avery, MacLeod, and McCarthy (8) and the description of the structure of DNA by Watson and Crick (9) indicated that DNA was the cellular target for activated chemical carcinogens and that mutations were key to understanding mechanisms of cancer. This led to defining the structure of the principal adducts in DNA by benzo(a)pyrene (10) and aflatoxin B1 (11). The concepts developed in investigating mechanisms of chemical carcinogenesis also led to discoveries that are relevant to other human conditions in addition to cancer, including atherosclerosis, cirrhosis, and aging.Global epidemiologic studies have indentified environmental and occupational chemicals as potential carcinogens. The most definitive epidemiologic studies have been those in which a small group is exposed to an inordinately large amount of a specific chemical, such as aniline dyes.Figure 1 illustrates exposure of individuals to residues from fossil fuel in chimneys, to tobacco smoke, and to fungi containing aflatoxin, and the identification of the responsible carcinogen(s). Active smoking and exposure to second-hand smoke are among the major causes of cancer mortality worldwide. Even after causative chemicals are identified, however, measurement of accumulated exposure of individuals in different environments remains an important challenge.The fact that genetic changes in individual cancer cells are essentially irreversible and that malignant changes are transmitted from one generation of cells to another strongly points to DNA as the critical cellular target modified by tobacco smoke and environmental chemicals. DNA damage by chemicals occurs randomly; the phenotypes of associated carcinogenic changes are determined by selection.Cancers caused by environmental agents frequently occur in tissues with the greatest surface exposure to the agents: lung, gastrointestinal tract, and skin. Recently, the study of chemical carcinogenesis has merged with studies on the molecular changes in cancer cells, thus generating biological markers to assess altered metabolic pathways and providing new targets for therapy. Although these are exciting areas, they may be peripheral to attacking the primary causes of the most common human cancers. As we catalog more and more mutations in cancer cells and more and more changes in transcription regulation, it becomes increasingly apparent that we need to understand what generates these changes. The fact that chemicals cause random changes in our genome immediately implies that our efforts need to be directed to quantifying these changes, reducing exposure, and developing approaches to chemoprevention.Chemical carcinogens cause genetic and epigenetic alterations in susceptible cells imparting a selective growth advantage; these cells can undergo clonal expansion, become genomically unstable, and become transformed into neoplastic cells. This classic view of carcinogenesis has its origin in experimental animal studies conducted in the mid 20th century. The first stage of carcinogenesis, tumor initiation, involves exposure of normal cells to chemical or physical carcinogens. These carcinogens cause genetic damage to DNA and other cellular macromolecules that provide initiated cells with both an altered responsiveness to their microenvironment and a proliferative advantage relative to the surrounding normal cells.Early in the field of chemical carcinogenesis, investigators recognized that perturbation of the normal microenvironment by physical means, such as wounding of mouse skin or partial hepatectomy in rodents (12, 13) or chemical agents, such as exposure of the mouse skin to certain phorbol esters (14), can drive clonal expansion of the initiated cells toward cancer. In the second stage, tumor promotion results in proliferation of the initiated cells to a greater extent than normal cells and enhances the probability of additional genetic damage, including endogenous mutations that accumulate in the expanding population. This classic view of two-stage carcinogenesis (14) has been conceptually important but also an oversimplification of our increasing understanding of the multiplicity of biological processes that are deregulated in cancer. In addition, an active debate continues on the relative contribution of procarcinogenic endogenous mechanisms—for example, free-radical–induced DNA damage (15), DNA depurination (16), DNA polymerase infidelity (17), and deamination of 5-methylycytosine (18)—compared with exposure to exogenous environmental carcinogens (19). The enhancement of carcinogens by epigenetic mechanisms such as halogenated organic chemicals and phytoestrogens (20), as well as the extrapolation of results from animal bioassays for identifying carcinogens to human cancer risk assessment, are also difficult to quantify (21). As discussed below, this debate is not merely an academic one, in that societal and regulatory decisions critical to public health are at issue. The identification of chemical carcinogens in the environment and occupational settings [benzo(a)pyrene and tobacco-specific nitrosamines in cigarette smoke, aflatoxin B1 (AFB1) residues from fossil fuel, vinyl chloride, and benzene] has led to regulations that have reduced the incidence of cancer.A timeline of selected experimental advances in chemical carcinogenesis that have important implications is presented in Fig. 2. First, the selected advances reflect the judgment of the authors and consultants, and remain to be modified by the readers, and, ultimately, by history. Second, the timeline shows the progression of results; an important observation generates new hypotheses that are tested by experiments with increasing mechanistic focus. Third, the timeline is punctuated with three important molecular discoveries (DNA structure, DNA sequence, and the PCR) that refocused experiments in chemical carcinogenesis (9, 22, 23). Fourth, many technological advances have allowed conceptual ideas to be experimentally tested, including the sensitive detection of chemical carcinogens by high-pressure liquid chromatography (24) and mass spectrometry (25), detection of DNA adducts by postlabeling (26) and by specific antibodies (27), transcriptional profiling by arrays (28, 29), and quantitation of mutagenicity of carcinogens using bacterial genetics (19).In the first half of the 20th century, the experimental focus was on identifying chemical carcinogens in complex mixtures, and on determining their metabolism and cellular targets. With the recognition that genes are encoded in DNA (9) and that DNA is transferred from one cellular generation to the next (30), research rapidly focused on the interaction of activated chemical carcinogens with DNA and on mutations that result from DNA alterations as well as the identification of key mutated (31) or deregulated genes including oncogenes and tumor suppressor genes (32). Underlying these studies was the expectation that delineation of mutated genes would identify them as specific targets for chemotherapy. The expectation that targeting individual mutated or rearranged gene products would be efficacious for cancer treatment has thus far been verified in only a limited number of situations, such as the use of imatinib for chronic myelogenous leukemia (33).The experimental landmarks highlighted in Fig. 2 frequently generated new experiments, and this progression has foretold some of our key concepts on the mechanisms of chemical carcinogenesis. An overriding concept has emerged that links DNA damage by reactive chemicals, the production of mutations by unrepaired DNA adducts, and the selection of cells harboring mutated genes that characterize the malignant phenotype. Studies on arylhydroxylamines provided a paradigm for tracing the metabolism of carcinogens to chemically reactive electrophiles that covalently bind to DNA. 2-Acetylaminofluorene (AAF) is metabolically activated by liver microsomal mixed–function oxygenases to N-hydroxy- and then to N-sulf oxy-AAF, a strong electrophile that forms covalent adducts with guanine moieties in DNA (34). AAF is not mutagenic in bacterial assays, whereas N-hydroxy-AAF is highly carcinogenic (34). N-hydroxy-AAF is rendered inactive by the formation of a glucuronide in the liver that is transported to the bladder and excreted (35). Unfortunately, it is subjected to acid hydrolysis in the bladder to yield active N-hydroxy-AAF, which is associated with human bladder cancer. Thus, the activation and detoxification of a chemical carcinogen in specific cells or tissues can be a major factor in determining tissue and host specificity.The testing of certain concepts in chemical carcinogenesis awaited the development of new technologies. For example, the concept of somatic mutations in cancer (1, 36) preceded by 40 years the establishment of DNA as the genetic material (8) and by 63 years the development of DNA sequencing methods (23) that directly showed clonal mutations in human cancer cells. Also, the mutator phenotype hypothesis formulated in 1974 (17) has been only recently experimentally verified (37).Many hypotheses are still under active investigation. These include the potential importance of carcinogen-protein interactions (38), carcinogen-induced reversion to stem cell–like phenotypes (39), inherited changes in gene expression (40, 41), direct action of nongenotoxic chemicals (42), and targeted interactions of carcinogens with specific genes such as TP53 (43–45). Other concepts focus on carcinogenesis mediated by RNA damage (46), RNA-templated DNA repair (47), specific metastasis genes (48, 49), and sequential clonal lineage pathways in cancer (50, 51).Emerging hypothesis such as anticarcinogens (52), overlapping pathways to malignancy (53), coordinated changes in gene expression (54), epigenetic silencing by chemical carcinogens (40, 55, 56), and oncogene addiction (57) are just beginning to be explored. Finally, there are concepts for which quantitation is lacking, yet have stood the test of time based on their inherent significance; these include the importance of anaerobic metabolism by tumors (58, 59) and the initiation of tumorigenesis by the generation of oxygen-reactive species (15).Although establishing DNA as the genetic material provided a structure that faithfully can be duplicated during each cell division, it rapidly became apparent that DNA was also subject to direct modification by X-rays (60), alkylating agents (61), and by an increasing number of environmental chemicals (62, 63). Changes in DNA by many chemical carcinogens are indirect; they first require activation by P-450 aryl hydroxylases into electrophiles to form covalent adducts with DNA and with other cellular macromolecules (64, 65). Many normally generated reactive molecules that are intermediates in metabolism modify many cellular molecules including DNA and therefore are mutagens and carcinogens. However, not all mutagens seem to be carcinogens. What was unanticipated was the magnitude of DNA modification by normal cellular processes in the absence of exposure to environmental mutagens (66, 67).The lability of DNA in an aqueous environment was first quantified by Lindahl and Nyberg, who measured the rates of depurination (16) and deamination (18) in solution under different conditions and extrapolated these results to those predicted to be present in human cells. They calculated that each normal cell could undergo >10,000 DNA damaging events per day. Endogenously generated modifications of DNA include methylation by S-adenosylmethione, modification by lipid peroxidation products, chlorination, glycosylation, oxidation, and nitrosylation (66–71). Reactive oxygen and nitrogen species are particularly relevant because the activated species are generated by host cells, and the process of resynthesis results in the replacement of >50,000 nucleotides per cell per day (68). To maintain our genomes, we have evolved a network of DNA repair pathways to excise altered residues from DNA (Fig. 3). A major consideration is the relative contribution of environmental and endogenous DNA damage to carcinogenesis. DNA damage by environmental agents would have to be extensive and exceed that produced by normal endogenous reactive chemicals to be a major contributor to mutations and cancer. This consideration underlines the difficulty in extrapolating risk of exposure to that which would occur at very low doses of carcinogens.Human cells possess an armamentarium of mechanisms for DNA repair that counter the extensiveness of DNA damage caused both by endogenous and environmental chemicals. These mechanisms include base excision repair (BER) that removes products of alkylation and oxidation (72–74); nucleotide excision repair (NER) that excises oligonucleotide segments containing larger adducts (75); mismatch repair that scans DNA immediately after polymerization for misincorporation by DNA polymerases (76); and oxidative demethylation (77), transcription-coupled repair (TCR) that preferentially repairs lesions that block transcription (78); double-strand break repair and recombination that avoids errors by copying the opposite DNA strand (79); as well as mechanisms for the repair of cross-links between strands (80, 81) that yet need to be established.Most DNA lesions are subject to repair by more than one pathway. As a result, only a minute fraction of DNA lesions escapes correction are present at the time of DNA replication and can direct the incorporation of noncomplementary nucleotides resulting in mutation (Fig. 3). Unrepaired DNA lesions initiate mutagenesis by stalling DNA replication forks or are copied over by error-prone trans-lesion DNA polymerases (82–84). Alternatively, incomplete DNA repair can result in the accumulation of mutations and mutagenic lesions, such as abasic sites (85).Damage to DNA by chemical carcinogens activates checkpoint signaling pathways leading to cell cycle arrest and allows time for DNA repair processes. In the absence of repair, cells can use special DNA polymerases that copy past DNA adducts (86, 87), or undergo apoptosis by signaling the recruitment of immunologic and inflammatory host defense mechanisms. The demonstration that each methylcholanthrene-induced tumor has a unique antigenic signature provided one of the earliest glimpses into the stochastic nature of cellular responses to carcinogens (88). The immunologic and inflammatory responses facilitate not only engulfment and clearance of damaged cells but also the resulting generation of reactive oxygen (89) and nitrogen radicals (90) that further damage cellular DNA.The concept that chronic inflammation can result in cancer is supported by Virchow's (91) histologic observation of inflammatory lymphocytes infiltrating tumors. Inflammation accompanying the "painting" of coal tar was described by Japanese pathologists in the earliest experimental study of chemical carcinogenesis (2). The classic tumor promoter, croton oil, and its most active ingredient, 12-O-tetradecanoylphorbol-13-acetate, are potent inflammatory agents. In addition to studies of "two-stage" skin carcinogenesis, other animal models have shown the synergistic interaction of chemical carcinogens with proinflammatory agents; for example, respiratory infection with influenza virus synergistically increases the lung cancer response in rats to a carcinogenic N-nitrosamine (92).Chronic inflammation can have a strong inherited basis, e.g. hemochromatosis, or can be acquired from infection by viruses, bacteria, or parasites or be associated with metabolic or physical conditions (93). Obesity has been considered to be a chronic inflammatory condition associated with multiple types of human cancer (94); gastric acid reflux causes chronic inflammation and can progress to Barrett's-associated esophageal adenocarcinoma (95); and colitis can progress to colon cancer (96, 97). Recent advances have begun to uncover the underlying mechanisms of the association between chronic inflammation and cancer.The identification of specific genes by allelic replacements and "knockouts" has facilitated the delineation of complex immune response networks that govern cellular responses to chemical carcinogens. The innate immune system is the first line of defense against pathogenic microorganisms and toxins and responds by generating free radicals, inflammatory cytokines, and the activation of the complement cascade (93, 98). In addition to reactive oxygen species, the past two decades have shown the significance of nitrogen-based free radicals, including nitric oxide and its derivatives (90, 93). The concentration and length of exposure can determine the seemingly paradoxical procarcinogenic and anticarcinogenic activities of free As be discussed in another in the chronic activation of the innate immune system is procarcinogenic and immune system is anticarcinogenic there is a to from an individual is exposed to a carcinogen to the detection of a For most there is an in cancer incidence as a of that tumor progression in a series of sequential This process has been most in colon cancer, with the progression from to to and to metastasis of cancers at different from to a sequential of mutations and genome mutations in DNA activation of of on and of This concept of sequential mutations has been by new including the of somatic mutations in and colon cancers and the demonstration that only a small fraction of colon cancers the three most frequently identified mutations this may identify potential not cancers a mutator a more stochastic cancer cell in a tumor of different and yet only a small of cells preferentially during to random mutations that a selective advantage for this concept is the demonstration that the of mutations in human cancers is greater than that in normal tissues in cell and adenocarcinoma of the colon The genetic of cancer cells produced by mutator mutations increases the that a tumor many cells to and is with the of of research in chemical carcinogenesis have provided a for the analysis of adducts and somatic mutations in as of carcinogen exposure. A paradigm for between of carcinogens exposure and a cancer risk is shown in Fig. a is a example of an environmental chemical carcinogen that has been using this a polycyclic aromatic (53), an aromatic and a tobacco-specific N-nitrosamine are other key epidemiologic studies a association between exposure and the incidence of studies of in multiple animal species, chemical and analysis of the identification of DNA adducts, and of mutagenic the for and to as a human carcinogen from these experimental animal and studies were then and to assess exposure and biological in studies conducted in of high exposure and high incidence of such as and The were and to the of the that is a human The between and was further by the association between exposure and a specific mutation in the nucleotide of of the tumor suppressor gene in In from and The a synergistic interaction between exposure or and of virus infection in the risk of was remain to be For example, the molecular of the synergistic interaction between and is still the and oxidative of to the gene incorporation in the genome of their of by advances in molecular are and they increasingly are being to understanding the interaction of chemical carcinogens with cellular and of DNA has facilitated the identification of specific genes mutated in human cancers. including mass to carcinogen with unprecedented and spectrometry is being with mutagenesis to specific alterations in DNA of the human genome and the identification of DNA enzymes the field of molecular in on individual susceptibility to carcinogens. analysis of carcinogen-induced alterations in the expression of both and the are that can molecules of carcinogens in cells, random mutations in individual cells, analysis of the of molecules and and and genetic to delineate complex pathways in cells. Underlying this progress in understanding chemical carcinogenesis is a cascade of advances in molecular that it to quantify DNA damage by chemical agents, and changes in gene the structure of DNA and the cell including carcinogenesis. in detection of DNA damage, including postlabeling of DNA (27), and mass spectrometry (25), have allowed the detection of a altered base in nucleotides using human DNA. This can be to DNA or RNA in a cell in cell including and it to assess changes in RNA and expression during carcinogenesis. these technologies it increasingly to pathways in cancer cells from to to to have made in identifying chemical carcinogens and their mechanisms of We have increasingly focused on DNA as a the fact at the cellular level, cancer is an inherited a cancer, a cancer. The efforts to chemicals as potential or human carcinogens are not but in most are in The need to identify chemical carcinogens in of human exposure and epidemiologic is on mechanistic and knowledge of and among animal species is a For example, the of in the by a not to be relevant to carcinogenesis, is initiated by epidemiologic verified by animal experiments, and by mechanistic and studies The between carcinogen exposure and the induction of cancer continues to be a of and public debate The of a is a in the of public health that to be as mechanistic accumulate in the field of chemical carcinogenesis has a history of that of cancer cancer risk assessment, public health and and occupational causes of cancer. The concepts of interactions and in the molecular of human cancer risk were generated by the of chemical carcinogenesis, cellular and molecular and cancer genetic in DNA repair and enzymes are of an inherited of in cancer susceptibility of the of cancer risk and detection are based on the knowledge of chemical carcinogenesis, including adducts, somatic and mutation carcinogen exposure and DNA with interactions can have synergistic for example, and in carcinogenesis. models of chemical carcinogenesis to a critical in the field of cancer and in our understanding the mechanisms of cancer and the of in in the field of chemical carcinogenesis remain to be stem cells mutated by chemical carcinogens and become of human chemical carcinogens epigenetic changes during These and other many to be formulated by to investigators in chemical carcinogenesis our understanding of carcinogenesis, and, as a result, cancer and potential of were Cancer and and by The Research of the Cancer for Cancer Research of of this were in by the of This therefore be in with to this selection of the major events in this review of the field are the primary of the with the of the The authors for many of which are of importance to the field of chemical carcinogenesis. We on this subject We for Fig. of chimney and for Fig. and of smoking and aflatoxin, and and for their critical

Phenols of virgin olive oil protects nuclear DNA against oxidative damage in HeLa cells

The relationship between the structure and the antioxidant activity of 21 hindered phenolic compounds was investigated by Rancimat and DPPH· tests. 3-tert-butyl-5-methylbenzene-1,2-diol is the strongest antioxidant in the Rancimat test but not in the DPPH· test because its two hydroxyl groups have very strong steric synergy. 2,6-Ditert-butyl-4-hydroxy-methylphenol exhibits a strong antioxidant activity as 2,6-ditertbutyl- 4-methoxyphenol does in lard. 2,6-Ditert-butyl-4- hydroxy-methylphenol also exhibits stronger activity than 2-tert-butyl-4- methoxyphenol. The methylene of 2,6-ditert-butyl-4-hydroxy-methylphenol can provide a hydrogen atom to active free radicals like a phenolic hydroxyl group does because it is greatly activated by both the aromatic ring and hydroxyl group. Five factors affect the antioxidant activities of the phenolic compounds: how stable the phenolic compound free radicals are after providing hydrogen atoms; how many hy drogen atoms each of the phenolic compounds can provide; how fast the phenolic compounds provide hydrogen atoms; how easily the phenolic compound free radicals can combine with more active free radicals, and whether or not a new antioxidant can form after the phenolic compound provides hydrogen atoms.

Objective: Oxidative DNA damages occur in the cells constantly exposed to reactive oxygen species that can originate from normal metabolic processes and from environmental agents. Accumulation of oxidative DNA damages has been observed in several pathologies, such as aging, carcinogenesis and degenerative diseases. In this study the hypothesis that gallic acid, one of the most distributed phenolics in plants, could prevent the H2O2-induced both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage was investigated. Methods: The cells were pretreated with gallic acid (28 µg/ml) for 4 h before the induction of oxidative stress by H2O2 (300 µM) exposure for 1 h. DNA damage was assessed in the mitochondrial DNA and two nuclear regions using quantitative polymerase chain reaction (qPCR) assay. Results: Pretreatment with gallic acid significantly reduced both nDNA and mtDNA damages occurred with H2O2 exposure. Conclusion: The results clearly demonstrate that gallic acid has a protective effect against oxidative damage for both nDNA and mtDNA in HeLa cells. Gallic acid is most likely to act as an antimutagenic/anticarcinogenic agent through the protection of genome against the damaging effect of chronic oxidative stress.

Effect of interaction between phenolic compounds and copper ion on antioxidant and pro-oxidant activities

Humic acid is a compound of colloidal,amorphous, and complex aromatic polymerwith functional groups of -COOH (carboxyl), -OH (phenol), and C = O (carbonyl). The presence of these functional groups provides a rationale for assuming that humic acids have a potential to produce phenolic, carboxylic and carbonylic compounds through cracking process. In this study the cracking was done by isolating humic acids from peat soil, and facilitated by a clay catalyst which had been activated. Humic acids were isolated by extracting the acids from the peat with NaOH and HCl. The characterization of humic acids included the determination of the ash content by gravimetric method and the analysis of the functional groups of humic acids by Infrared spectrometer (FTIR). The clay to be activated was shaped into two forms, pellets and 20-40 mesh granules. The clay was activated by immersing it in HCl and NH4NO3, and then calcined. The characterization of catalysts included the determination of acidity and the Si/Al ratio gravimetrically, as well as the analysis of the pore volume, maximum pore radius, surface area and average pore radius by Surface Area Analyzer NOVA-1000. Humic acid cracking was performed by a fixed-bed reactor system at a temperature of 400°C. The Liquid smoke, the product of cracking, was analyzed by GC and GC-MS to determine the number of compounds and major compounds contained in the liquid smoke. The results show that the isolated humic acid had ash content of 9.10%. Activated clay had acidity and Si/Al ratio higher than the clay before actifated. Based on the analyses of GC and GC-MS it can be found out that the major compounds contained in liquid smoke, the product of humic acid cracking with 20-40 mesh catalyst at a temperature of 400°C were phenolic compounds (74.56%), and no carboxylic and carbonylic compounds as the major compounds. The activated clay can be used as the catalyst for humic acid cracking.

The potential for DNA damage and the activation of specific oncogenic pathways that cause inflammation are present in a wide range of physical, chemical, and biological variables that are constantly present in human beings. According to certain theories, chemical carcinogens are the primary etiological factor in cancer. These substances interact either or non-covalently with the DNA, RNA, and proteins in human tissue, which helps to initiate carcinogenesis, a process in which genetic mutation and changes to the transcription of the genome take precedence. These carcinogens act as cancer cell growth initiators or promoters. When DNA, RNA, or proteins are alkylated, covalent connections are first formed with them and then the promoting action occurs. The process involves numerous molecular and cellular changes that turn normal cells into plastic cells. Although it is hypothesized that these endogenous chemical processes could cause DNA damage by inducing gene changes with the aid of reactive oxygen species. This review's focus is on the basic mechanism and metabolism of chemical carcinogenesis. Chemical carcinogens are supposedly considered to be the key etiological factor of malignancy. The covalent or non-covalent bonds between these chemical and the DNA, RNA, and proteins of human tissue help in the initiation of carcinogenesis wherein, genetic mutation and alteration in the genome transcription supervenes. These carcinogens behave as initiators or promoters of cancer cell growth. Alkylation of DNA, RNA, or proteins and the formation of covalent bonds with them begin initially followed by the promoting effect. Numerous molecular and cellular events causing the transformation of normal cells into neoplastic cells occur in the process. It is assumed though those endogenous molecular pathways could instigate mutations in respective genes with the support of reactive oxygen species, thus leading to DNA damage. Thus, this review deals with the basic mechanism and metabolism of chemical carcinogenesis.

To understand the mechanism of nucleotide excision repair (NER), one of the major human DNA repair pathways, we have set up a DNA repair system in which a linear damaged DNA substrate is immobilized by its terminus. By isolating functionally active intermediate complexes, our data dissect the ordered arrival and displacement of NER factors in the progress of the dual incision step. We describe (i) the role of ATP in remodelling the NER-initiating complex of XPC/TFIIH/damaged DNA as a prerequisite for the recruitment of the next NER factors; (ii) the coordination between damage removal and DNA resynthesis and the release of XPC-HR23B, TFIIH and XPA upon arrival of XPG and XPF-ERCC1, respectively; (iii) how RPA remains associated with the excised DNA initiating the assembly of resynthesis factors such as PCNA; (iv) the recycling of XPC-HR23B, TFIIH and XPA in the NER; and the shuttling of TFIIH between NER and transcription. Thus, our findings define multiple functions of NER factors to explain the molecular basis of human NER disorders.

In this study, the multifaceted toxicity caused by zinc sulfate (ZnSO4) and the protective potential of Helichrysum arenarium L. extract against this toxicity were investigated using the model organism Allium cepa. In this context, changes in growth, cytogenetic, biochemical and histological parameters, as well as DNA damage were investigated in groups of A. cepa L. exposed to H. arenarium extract (50 and 100 mg/L), ZnSO4 (140mg/L), and their combinations, respectively. The phenolic profile of the extract was also evaluated through LC-MS/MS analysis. ZnSO4 treatment reduced growth, mitotic index (MI) and chlorophyll pigment levels. Chromosomal aberrations (CAs) and micronucleus (MN) formation as well as lipid peroxidation and antioxidant enzyme (superoxide dismutase and catalase) activities increased following the ZnSO4 exposure. DNA damage, as measured by the level of DNA fragmentation, also increased significantly in response to ZnSO4. While both doses of H. arenarium caused no harm when administered alone, when combined with ZnSO4, the toxic effects were significantly mitigated. In particular, the improvement in growth, the reduction in DNA and membrane damage, the maintenance of chromosomal stability and the recovery of chlorophyll levels suggested a protective effect of the extract. The therapeutic potential of the extract was dose-dependent. Phenolic profile analysis revealed that the extract is rich in phenolic compounds such as apigenin, chlorogenic acid, and luteolin. Given the antioxidant and antigenotoxic potential of these compounds, it is suggested that the extract's bioprotective effect may be attributable to its phenolic content. This study suggests that H. arenarium extract can exert a multifaceted protective effect against zinc-induced toxicity, thereby offering a new perspective on the use of plant-derived natural compounds against heavy metal stress.

Our studies are currently focused on the constituents of tea. Tea is a flavorful healthy food whose anticancer properties are the subject of many ongoing investigations. The main components of tea are phenolic compounds such as catechins, as well as caffeine. Theaflavins are the components of black tea. Theaflavins are phenolic compounds; also, strictinin is a hydrolyzable tannin of tea (fig. 1). It has been reported that tea extracts show anticancer effects, and these extracts contain many kinds of phenolic components. On the other hand, Professors Fujiki and Yoshida et al.1,2 reported that hydrolyzable tannins, geraniin, penta-O-galloyl-β-D-glucose, etc., showed inhibitory effects on tumor promotion induced by teleocidin on mouse epidermis. In this case, the initiator of carcinogenesis was 7,12-dimethyl-benz [α] anthracene (DMBA). This suggested that hydrolyzable tannins have antitumor promotion effects. Therefore, we focused on the inhibitory effects of hydrolyzable tannins on tumor promoting activities in other assay systems.