![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Lombardi Cancer Center, Georgetown University Medical Center, Washington, D.C.
2 To whom correspondence should be addressed. E-mail: pgs2{at}georgetown.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT Mutagenesis and carcinogenesisMethods to study food...Aflatoxin B1Polycyclic aromatic hydrocarbonsN-NitrosaminesHeterocyclic aminesPerspectivesLITERATURE CITED |
|---|
KEY WORDS: • biomarkers • diet assessment • epidemiology • mutagens • nutrition
Foods and dietary behaviors are thought to increase cancer risk, which is due in part to the consumption of food mutagens. These mutagens contribute to cancer along the route of exposure (oral cavity, esophagus, gastrointestinal tract) and in organs that are distant to the route of exposure (e.g., liver). Although there are some clearly identified food mutagens (e.g., aflatoxin) and other suspected mutagens (e.g., N-nitrosamines or heterocyclic amines), we do not know what if any mutagens cause cancers that have been associated with different types of diet (e.g., high fat). On the other side, and not reviewed herein, are dietary constituents that reduce the risk of cancer, in some cases by decreasing the effects of food mutagens, and dietary compounds that might indirectly affect the cellular control of DNA regulation via methylation.
Sporadic cancers result from gene-environment interactions where the environment includes endogenous and exogenous exposures (1,2). In this article, we define environment to include dietary exposures and the exposures that occur at the cellular and macromolecular levels. Food mutagens cause different types of DNA damage, namely, nucleotide alterations and gross chromosomal aberrations. Most mutagens begin their action at the DNA level by forming carcinogen-DNA adducts (3–5), which result from the covalent binding of a carcinogen or part of a carcinogen to a nucleotide. However the effects of food mutagens in carcinogenesis can be modified by heritable traits, namely, low-penetrant genes that affect mutagen exposure of DNA through metabolic activation and detoxification or cellular responses to DNA damage through DNA repair mechanisms or cell death.
This article reviews the role of food mutagens in mutagenesis and carcinogenesis and how their effects are modified by heritable traits; it also discusses how to identify and evaluate the effects of food mutagens. There are data to indicate that food mutagens and carcinogens affect specific organs rather than affecting every organ in the body. Separately foods contain many substances that likely reduce cancer risk, such as antioxidants or some types of fibers. These are not reviewed herein, but it should be recognized that nutritionally related cancers occur through an imbalance of carcinogenesis and anticarcinogenesis.
Mutagenesis is not the only pathway that links dietary exposures and cancers. There is growing evidence that epigenetic factors including changes in DNA methylation patterns are causing cancer (6) and can be modified by dietary components (7). Also DNA damage may be indirect by triggering oxidative DNA damage (8,9).
|
Mutagenesis and carcinogenesis |
|---|
|
TOPABSTRACTMutagenesis and carcinogenesisMethods to study food...Aflatoxin B1Polycyclic aromatic hydrocarbonsN-NitrosaminesHeterocyclic aminesPerspectivesLITERATURE CITED |
|---|
Some dietary exposures can plausibly modify the effects of food mutagens. For example, alcoholic beverages induce an isoform of cytochrome P450 (CYP)2E1,3 which metabolically activates N-nitrosamines, whereas the ingestion of vitamin C prevents the formation of N-nitrosamines. Exposure to certain food mutagens such as polycyclic aromatic hydrocarbons (PAH) can induce CYP1A1, which then causes increased metabolic activation of these compounds.
Cancer-related genes can be classified as protooncogenes and tumor-suppressor genes. The former are normally functioning genes that regulate normal cell growth, replication and differentiation but contribute to carcinogenesis when they are mutated in such a way that leads to uncontrolled gene expression and cellular proliferation. Tumor-suppressor genes also regulate normal cell growth, replication and differentiation but contribute to carcinogenesis when a mutation leads to loss of function. More recently cancer-related genes have been classified as caretaker, gatekeeper and landscaper genes (11,12). Caretaker genes are responsible for maintaining genomic integrity (e.g., DNA repair, metabolic activation and detoxification), and when mutated they increase the probability of mutations in other genes. The gatekeeper genes are responsible for cell-cycle control, signal transduction and replication. When mutated, these genes allow for selective clonal expansion. Landscaper genes are responsible for providing signals to adjacent cells. Although the classification of these genes was originally proposed in the context of high-penetrant genes and familial cancer syndromes, the concept is also applicable to low-penetrant genes and gene-environment interactions (2). Consideration of the specific genetic functions and how they are mutated should lead to different paradigms in cancer risk and statistical models for approaching gene-gene interactions.
The effects of food mutagens on caretaker and gatekeeper genes can theoretically be modulated by interindividual variation in function of any enzyme involved in DNA damage and response (metabolic activation, detoxification, DNA repair, cell-cycle control, apoptosis, etc.). For food mutagens that lead to cancer, interindividual variation is governed by genetic polymorphisms where the frequency of the genetic variant is > 1% in the population of interest. Sporadic cancer risk is usually modified by genetic polymorphisms in low-penetrant genes (risk of the genetic trait is > 1 but < 2), and the risks of these genes are more often identified in the context of exposure and not as a main effect. It is important to realize that although the increase in cancer risk associated with polymorphisms in low-penetrant genes is small, the attributable risk in the population is large due to the high frequency of the variants (2). Most research for genetic susceptibilities has focused on carcinogen metabolism and detoxification (13–15), and more recently there has been a focus on DNA repair (16). Clearly research efforts need to expand toward the study of gatekeeper and other caretaker genes.
|
Methods to study food mutagens |
|---|
|
TOPABSTRACTMutagenesis and carcinogenesisMethods to study food...Aflatoxin B1Polycyclic aromatic hydrocarbonsN-NitrosaminesHeterocyclic aminesPerspectivesLITERATURE CITED |
|---|
|
High-throughput screening methodologies for the mechanistic and toxicological endpoints are being developed for use in experimental systems and epidemiological studies (30–32). High throughput can refer to the ability to identify a large number of cellular effects in a single experiment or the application of an assay in a large number of subjects. The new methods include large-scale genomic screens based on microarrays (33,34) and proteomic screens based on 2-D gel electrophoresis with mass spectrometric detection (35,36) or surface-enhanced laser desorption/ionization (37). The genomics and proteomic methods are plausibly useful to screen for toxicological effects and earlier carcinogenic events in vitro and in in vivo experimental studies (38,39). Some methods can be applied to large numbers of epidemiological subjects (40). However the interpretation of data when there are a large number of data points for both known and unknown genes or proteins challenges our current statistical models and requires novel approaches to the interpretation of data. For example, the best methods for determining unique patterns of expression that are representative of a particular toxic effect or clustering responses that predict a combination of effects are only now being tested. These methods use either cluster data based on statistical relationships or biological pathways. Other new advances are providing researchers with powerful tools for analysis of diet-related carcinogenic pathways. The combinatorial synthesis of chemical compounds has tremendously increased the production of novel chemicals and drugs including dietary supplements (41–43). These provide new opportunities to expand cancer research as well as the understanding of carcinogenesis.
Biomarker assays are frequently used to assess exposure to food mutagens and how the body responds to those exposures. Any assay that is performed on a biological fluid or tissue can be considered a biomarker assay. Importantly exposure in this context refers to exposure at the cellular and macromolecular levels rather than what might be in foodstuffs or reflected in dietary behaviors. An important conceptual approach is to consider the biologically effective dose of a mutagen (44), which is a measure of the effect of the mutagen in DNA (i.e., carcinogen-DNA adducts, nucleotide alterations, chromosomal aberrations) or its surrogate. The biologically effective dose is a phenotype of a person's response to the exposure; namely, the net result of metabolic activation and detoxification, a lack of DNA repair and a lack of triggered cell death. Because epidemiological studies that necessarily rely on a subject's recall of dietary behavior present some challenges to identifying food-mutagen intake, the use of internal dosimeters and biomarkers can reduce this limitation by improving exposure classification at the macromolecular level and ultimately improving risk assessments (45,46). Currently questionnaires and biomarker assays are mostly complementary and are most powerful when used together.
The use of biomarkers within epidemiology improves exposure assessments (e.g., characterizing low-dose exposures or low-risk populations), provides a relative contribution of individual chemical carcinogens from complex mixtures (e.g., N-nitrosamines) and estimates the total burden of a particular exposure when there are numerous sources [e.g., benzo(a)pyrene (BaP) from diet, air, tobacco and occupation] (47). In general biomarkers are intuitively more informative and should be better disease risk markers. However often these assays are technically limited and target tissue is difficult to obtain. Although surrogate markers and the use of surrogate tissues are popular because they reduce technical challenges, only a small effort has been undertaken to ensure that the surrogates actually reflect the effects of interest. Correlative studies are needed, and therefore assays that directly measure the effects of interest in target organs also are needed even though these might be technically limited, labor intensive or used in small numbers of subjects. As an example, the relationship of surrogate markers such as carcinogen-DNA adducts in blood to the target organ has been partially established (48,49). Recently the emphasis on methodology and quality control in research laboratories that focus on mutagen-related biomarkers has been improving.
A variety of assays are available for identifying carcinogen-macromolecular adducts in human tissues (50–56). These include the 32P-postlabeling assay/nucleotide chromatography, immunoassays such as immunohistochemistry, fluorescence spectroscopy, gas chromatography/mass spectroscopy and electrical chemical detection. Recent methods take advantage of new methodologies including radiolabels detectable at very low doses (56) and fluorescent detectors. Each of these adduct assays has its usefulness and limitations, and all are challenged by sensitivity and/or specificity.
Other biomarker assays have been used to assess the biological consequences of mutagen exposure. A nonspecific assay is to measure urine mutagenicity, where extracts of human urine are used in the Salmonella mutation assay. Also sister chromatid exchanges and chromosomal aberrations can be measured in cultured lymphocytes, but these are probably too nonspecific to be useful in assessing dietary effects.
The study of mutations in the p53 tumor-suppressor gene is uniquely suited for the study of cancer etiology, exposure and susceptibility (57), because p53 is involved in many cellular processes including maintenance of genomic stability, programmed cell death (apoptosis), DNA repair and cell-cycle control (58,59). The p53 mutation frequency in cancer varies by organ site and histological subtype (60), which indicates that cancers occur through different pathways and exposures at the cellular level. There are several examples of specific carcinogenic exposures that are linked to cancers via a p53 mutational mechanism particularly for dietary aflatoxin B1 exposure and a consistent finding of mutations in the third nucleotide pair of codon 249 of liver cancers in regions with endemic exposure to aflatoxin B1 (61,62). Combinations of exposures also can lead to different outcomes in the same organ site. An interactive effect of hepatitis B exposure and aflatoxins increase the risk of mutations (63).
Biomarker assays can be useful in confirming a hypothesis regarding etiological relationships. For example, although alcoholic beverages are associated with oral cavity cancers and weakly with breast cancers (64–66), the carcinogenic agent remains unknown. Ethanol is oxidized to acetaldehyde, which is weakly mutagenic. This oxidation is governed by alcohol dehydrogenases (ADH) and the ADH3 gene is polymorphic. In different studies, the allele corresponding to increased oxidation capacity was associated with both oral cavity (67) and breast (68) cancers. Separately a role for oxidative damage in breast cancer is supported by studies of the manganese superoxide dismutase gene; polymorphic variants increased breast cancer risk, which was greatest in persons with low antioxidant food intake (69).
Examples of biomarkers associated with specific exposures and target organs are shown in Table 2.
|
|
Aflatoxin B1 |
|---|
|
TOPABSTRACTMutagenesis and carcinogenesisMethods to study food...Aflatoxin B1Polycyclic aromatic hydrocarbonsN-NitrosaminesHeterocyclic aminesPerspectivesLITERATURE CITED |
|---|
Several biomarker assays for aflatoxin exposure have been developed (46,88). Although it would be preferable to measure the biologically effective dose in the liver, because this is the target organ, it is not practical. Thus methods have focused on blood and urine markers. Levels of aflatoxin adducts vary among areas of low and high contamination (89). Measurements of the adduct or its metabolite in the urine indicate a dose-response effect for aflatoxin B1 exposure and liver cancer (46,63). The effect is multiplicative in persons infected with hepatitis B or C (90,91).
The detoxification of aflatoxin exo-8,9-epoxides by conjugation to glutathione has prompted studies of oltipraz as a chemoprotective agent, because it is an inducer of glutathione transferase M1 enzyme (92). The preliminary results from a phase II clinical trial show a significant reduction in the biomarkers of aflatoxin damage in the oltipraz-treated group (93).
|
Polycyclic aromatic hydrocarbons |
|---|
|
TOPABSTRACTMutagenesis and carcinogenesisMethods to study food...Aflatoxin B1Polycyclic aromatic hydrocarbonsN-NitrosaminesHeterocyclic aminesPerspectivesLITERATURE CITED |
|---|
PAH food exposure and cancer risk have received little attention. The effects of PAH exposure, which are measured mostly in other settings (e.g., tobacco smoking and the workplace), indicate that the target organs for PAH compounds are the lung, oropharynx, breast and genitourinary and gastrointestinal tracts. Thus biomarkers for the assessment of PAH would focus on studies in these organs or surrogate tissues for these organs.
In laboratory animal studies, diets with PAH consistently induce foregut tumors and also can induce lung tumors (100–105). In humans there is some evidence for association of dietary PAH exposure with colon cancer (106,107). Animal (108,109) and human studies (110) suggest that dietary PAH is distributed to other organs besides the locally exposed tissues, so it is plausible to consider that dietary PAH might contribute to lung or breast cancer risk, for example. Although the dietary contribution of PAH to the total body burden may be sizeable (111,112), the ubiquitous presence of PAH in the environment (113) and the presence of other carcinogens in the same foods (114,115) makes the interpretation of epidemiological studies of cancer risk due to dietary PAH difficult. It may be possible to distinguish PAH exposures in diet from smoking by measuring biomarkers specific to each [e.g., simultaneous measurement of 1-hydroxypyrene to evaluate total PAH intake (116) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) to evaluate the contribution due to smoking (51)]. In addition, dietary PAH is invariably a complex mixture of compounds with hard-to-predict metabolic and carcinogenic consequences.
Benzo(a)pyrene is the best-characterized PAH compound available from the diet. The bay-region diol epoxide binds to DNA mostly as the N2-deoxyguanosine adduct (117). The metabolic activation by the CYP1A (118) and CYP1B (119,120) classes of enzymes are required for adduct formation. BaP adducts can be quantified by several sensitive methods (56,121,122). Other methods exist for detecting PAH metabolites [e.g., urinary BaP-tetrol (123) and 3-hydroxybenzo(a)pyrene (124)]. BaP adducts estimate the biologically effective dose and suggest a link to cancer risk in the lung (125,126); they are also associated with site-specific hotspot mutations in the p53 tumor-suppressor gene (60,127) and mutations observed in lung cancer of smokers (128). Similar evidence for dietary PAH-associated cancer should be sought, for example, in gastrointestinal cancers.
|
N-Nitrosamines |
|---|
|
TOPABSTRACTMutagenesis and carcinogenesisMethods to study food...Aflatoxin B1Polycyclic aromatic hydrocarbonsN-NitrosaminesHeterocyclic aminesPerspectivesLITERATURE CITED |
|---|
Experimental animal models strongly support the carcinogenic properties of dietary N-nitrosamines (130). In fact there is a large concordance between animal species and strains albeit with different organ specificity, type of compound and dose (139). Cancer of the lung, liver, kidney, mammary gland, stomach, pancreas, bladder or esophagus has been observed (140). These sites also are considered to be the target organs in humans, and so biomarker assays are best suited for them.
The N-nitrosamines are a large group of compounds with a common carcinogenic mechanism. N-nitrosodimethylamine frequently is formed as a result of dietary exposures. N-nitrosodimethylamine undergoes enzymatic hydroxylation and subsequent hydrolysis to an aldehyde and a monoalkylnitrosamine that rearranges and releases a carbocation that is reactive toward DNA bases (141,142). The hydroxylation is catalyzed mainly by CYP2E1 (143,144), but other cytochrome P450 isoforms including CYP2A6 have been implicated (14,145).
The O6-methylguanine is mostly responsible for the mutagenicity and carcinogenicity of alkylating agents (146,147). The O6-methylguanine leads to GC
AT transitions in cell-culture (148) and animal (149) models if not repaired by the O6-methylguanine methyltransferase (150,151). A specific mutation was observed in codon 12/13 of ras oncogene in animals exposed to alkylating agents (152) [later evidence suggests that this may have been due to clonal selection rather than mutation (153)] and in human gastrointestinal tumors of unknown etiology (154). Although the O6-methylguanine is a promutagenic lesion, it is technically easier to measure the 7-methylguanine, which is not promutagenic, as a surrogate marker for exposure and genetic susceptibility, because the 7-methylguanine occurs at levels 
10-fold higher. Human studies of N-nitrosamine adducts in different tissues and the use of susceptibility markers should help elucidate the risks of N-nitrosamine exposures.
|
Heterocyclic amines |
|---|
|
TOPABSTRACTMutagenesis and carcinogenesisMethods to study food...Aflatoxin B1Polycyclic aromatic hydrocarbonsN-NitrosaminesHeterocyclic aminesPerspectivesLITERATURE CITED |
|---|
The parent heterocyclic compounds, their metabolites and biologically effective doses determined by DNA and protein adducts have been measured in human studies using accelerator mass spectrometry (55,169–171) and a variety of other very sensitive analytical methods (55,172,173). There is also good epidemiological evidence correlating the consumption of foods containing a high content of heterocyclic amines with colon cancer (174–176) although this correlation is not consistent (177). It appears that the mutations in the APC and p53 tumor-suppressor genes suggest a connection to the exposure to heterocyclic amines (178), but further research is needed. Although the elimination of heterocyclic amines from the diet seems impractical, exposures can be reduced by cooking foods at lower temperatures (156,179). Possible chemopreventive interventions based on current understanding of the carcinogenic mechanism have been also proposed (180,181).
|
Perspectives |
|---|
|
TOPABSTRACTMutagenesis and carcinogenesisMethods to study food...Aflatoxin B1Polycyclic aromatic hydrocarbonsN-NitrosaminesHeterocyclic aminesPerspectivesLITERATURE CITED |
|---|
Newer technologies also will allow investigators to measure many types of effects simultaneously. Although the costs of these methods (such as microarray expression approaches) are prohibitive for large numbers of assays, the ability to observe many changes in a single experiment can be very powerful. Similarly some array methods can be applied to a large number of subjects, and once established (e.g., a tumor array), the results can be rapidly determined for a large number of makers. The current challenges include the lack of approaches to make meaningful interpretations of the data, and the varying of the data-interpretation methods depending on whether the data was collected with a priori hypotheses or through screening methods. Although these newer methods may be more powerful than other methods, the need for careful validation of the biomarker is still great.
This article has focused on the most commonly studied food mutagens, but many others exist in food as do agents that reduce cancer risk. The integrated consideration of all of these remains problematic because of the complex nature of the exposure and the documentation of dietary habits, and each of our research methods has strengths and limitations. The new methods for assessing biomarkers will not replace our established epidemiological methods such as questionnaires and measurements of mutagens in foodstuffs, but they will be complementary.
Biomarkers that assess the effects of food mutagens range from markers of susceptibility to phenotypic markers of effect (p53 mutations, overexpression of enzymes, etc.). Employing multiple biomarkers within well-designed epidemiological studies can be useful in identifying new food mutagens or the role of previously established mutagens.
|
FOOTNOTES |
|---|
4 Abbreviations used: ADH, alcohol dehydrogenase; BaP, benzo(a)pyrene; CYP, cytochrome P450; PAH, polycyclic aromatic hydrocarbon
|
LITERATURE CITED |
|---|
|
TOPABSTRACTMutagenesis and carcinogenesisMethods to study food...Aflatoxin B1Polycyclic aromatic hydrocarbonsN-NitrosaminesHeterocyclic aminesPerspectivesLITERATURE CITED |
|---|
1. Perera, F. P. (1997) Environment and cancer: who are susceptible? Science 278: 1068–1073.
2. Shields, P. G. & Harris, C. C. (2000) Cancer risk and low penetrance susceptibility genes in gene-environment interactions. J. Clin. Oncol. 18: 2309–2315.
3. Dipple, A. (1995) DNA adducts of chemical carcinogens. Carcinogenesis 16: 437–441.
4. Harris, C. C. (1991) Chemical and physical carcinogenesis: advances and perspectives for the 1990s. Cancer Res. 51(suppl. 18): 5023S–5044S.
5. Strickland, P. T. & Groopman, J. D. (1995) Biomarkers for assessing environmental exposure to carcinogens in the diet. Am. J. Clin. Nutr. 61(suppl. 3): 710S–720S.
6. Lipkin, M., Reddy, B., Newmark, H. & Lamprecht, S. A. (1999) Dietary factors in human colorectal cancer. Annu. Rev. Nutr. 19: 545–586.[Medline]
7. Dumont, N. (1999) Genetic and epigenetic contributions to colorectal cancer. APMIS 107: 711–722.[Medline]
8. Halliwell, B. (1999) Oxygen and nitrogen are pro-carcinogens. Damage to DNA by reactive oxygen, chlorine and nitrogen species: measurement, mechanism and the effects of nutrition. Mutat. Res. 443: 37–52.[Medline]
9. Ames, B. N. & Gold, L. S. (1998) The causes and prevention of cancer: the role of environment. Biotherapy 11: 205–220.[Medline]
10. Harris, C. C. (1989) Interindividual variation among humans in carcinogen metabolism, DNA adduct formation and DNA repair. Carcinogenesis 10: 1563–1566.
11. Adamson, R. H., Thorgeirsson, U. P., Snyderwine, E. G., Thorgeirsson, S. S., Reeves, J., Dalgard, D. W., Takayama, S. & Sugimura, T. (1990) Carcinogenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in nonhuman primates: induction of tumors in three macaques. Jpn. J. Cancer Res. 81: 10–14.[Medline]
12. Kinzler, K. W. & Vogelstein, B. (1998) Landscaping the cancer terrain. Science 280: 1036–1037.
13. Perera, F. P. (1996) Molecular epidemiology: insights into cancer susceptibility, risk assessment, and prevention. J. Natl. Cancer Inst. 88: 496–509.
14. Gonzalez, F. J. & Gelboin, H. V. (1993) Role of human cytochrome P-450s in risk assessment and susceptibility to environmentally based disease. J. Toxicol. Environ. Health 40: 289–308.[Medline]
15. Yuspa, S. H. & Shields, P. G. (1997) Etiology of cancer: chemical. In: Cancer: Principles and Practice of Oncology (DeVita, V. T., Hellman, S. & Rosenberg, S. A., eds.), pp. 185–202. Lippincott-Raven, Philadelphia, PA.
16. Tsuda, H., Hirohashi, S., Shimosato, Y., Ino, Y., Yoshida, T. & Terada, M. (1989) Low incidence of point mutation of c-Ki-ras and N-ras oncogenes in human hepatocellular carcinoma. Jpn. J. Cancer Res. 80: 196–199.[Medline]
17. Hill, A. B. (1965) The environment and disease: association or causation. Proc. R. Soc. Med. 58: 295–300.[Medline]
18. Szeliga, J. & Dipple, A. (1998) DNA adduct formation by polycyclic aromatic hydrocarbon dihydrodiol epoxides. Chem. Res. Toxicol. 11: 1–11.[Medline]
19. Marnett, L. J. (1999) Lipid peroxidation-DNA damage by malondialdehyde. Mutat. Res. 424: 83–95.[Medline]
20. Balmain, A. & Harris, C. C. (2000) Carcinogenesis in mouse and human cells: parallels and paradoxes. Carcinogenesis 21: 371–377.
21. Thorgeirsson, S. S., Factor, V. M. & Snyderwine, E. G. (2000) Transgenic mouse models in carcinogenesis research and testing. Toxicol. Lett. 112/113: 553–555.
22. Epstein, C. J., Martin, G. M., Schultz, A. L. & Motulsky, A. G. (1966) Werner's syndrome: a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore) 45: 177–221.[Medline]
23. Waters, M. D., Stack, H. F. & Jackson, M. A. (1999) Short-term tests for defining mutagenic carcinogens. IARC Sci. Publ. 146: 499–536.
24. Crump, K. S., Krewski, D. & Van Landingham, C. (1999) Estimates of the proportion of chemicals that were carcinogenic or anticarcinogenic in bioassays conducted by the National Toxicology Program. Environ. Health Perspect. 107: 83–88.[Medline]
25. Haseman, J. K. & Lockhart, A. M. (1993) Correlations between chemically related site-specific carcinogenic effects in long-term studies in rats and mice. Environ. Health Perspect. 101: 50–54.[Medline]
26. Hengstler, J. G., Van der Burg, B., Steinberg, P. & Oesch, F. (1999) Interspecies differences in cancer susceptibility and toxicity. Drug Metab. Rev. 31: 917–970.[Medline]
27. Gold, L. S., Manley, N. B. & Ames, B. N. (1992) Extrapolation of carcinogenicity between species: qualitative and quantitative factors. Risk Anal. 12: 579–588.[Medline]
28. Grisham, J. W. (1997) Interspecies comparison of liver carcinogenesis: implications for cancer risk assessment. Carcinogenesis 18: 59–81.
29. Tennant, R. W., French, J. E. & Spalding, J. W. (1995) Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ. Health Perspect. 103: 942–950.[Medline]
30. Sundberg, S. A. (2000) High-throughput and ultra-high-throughput screening: solution- and cell-based approaches. Curr. Opin. Biotechnol. 11: 47–53.[Medline]
31. Tawata, M., Aida, K. & Onaya, T. (2000) Screening for genetic mutations. A review. Comb. Chem. High Throughput Screen. 3: 1–9.[Medline]
32. Nestler, H. P. & Liu, R. (1998) Combinatorial libraries: studies in molecular recognition. Comb. Chem. High Throughput Screen. 1: 113–126.[Medline]
33. Pollack, J. R., Perou, C. M., Alizadeh, A. A., Eisen, M. B., Pergamenschikov, A., Williams, C. F., Jeffrey, S. S., Botstein, D. & Brown, P. O. (1999) Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat. Genet. 23: 41–46.[Medline]
34. DeRisi, J., Penland, L., Brown, P. O., Bittner, M. L., Meltzer, P. S., Ray, M., Chen, Y., Su, Y. A. & Trent, J. M. (1996) Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat. Genet. 14: 457–460.[Medline]
35. Steiner, S. & Anderson, N. L. (2000) Expression profiling in toxicology—potentials and limitations. Toxicol. Lett. 112/113: 467–471.
36. Blackstock, W. P. & Weir, M. P. (1999) Proteomics: quantitative and physical mapping of cellular proteins. Trends Biotechnol. 17: 121–127.[Medline]
37. Merchant, M. & Weinberger, S. R. (2000) Recent advancements in surface-enhanced laser desorption/ionization-time of flight-mass spectrometry. Electrophoresis 21: 1164–1177.[Medline]
38. Scherf, U., Ross, D. T., Waltham, M., Smith, L. H., Lee, J. K., Tanabe, L., Kohn, K. W., Reinhold, W. C., Myers, T. G., Andrews, D. T., Scudiero, D. A., Eisen, M. B., Sausville, E. A., Pommier, Y., Botstein, D., Brown, P. O. & Weinstein, J. N. (2000) A gene expression database for the molecular pharmacology of cancer. Nat. Genet. 24: 236–244.[Medline]
39. Alizadeh, A., Eisen, M., Davis, R. E., Ma, C., Sabet, H., Tran, T., Powell, J. I., Yang, L., Marti, G. E., Morre, D. T., Hudson, J. R., Chan, W. C., Greiner, T., Weisenburger, D., Armitage, J. O., Lossos, I., Levy, R., Botstein, D., Brown, P. O. & Staudt, L. M. (1999) The Lymphochip: a specialized cDNA microarray for the genomic-scale analysis of gene expression in normal and malignant lymphocytes. Cold Spring Harb. Symp. Quant. Biol 64: 71–78.[Medline]
40. Ahrendt, S. A., Halachmi, S., Chow, J. T., Wu, L., Halachmi, N., Yang, S. C., Wehage, S., Jen, J. & Sidransky, D. (1999) Rapid p53 sequence analysis in primary lung cancer using an oligonucleotide probe array. Proc. Natl. Acad. Sci. U.S.A. 96: 7382–7387.
41. Dolle, R. E. & Nelson, K. H., Jr. (1999) Comprehensive survey of combinatorial library synthesis: 1998. J. Comb. Chem. 1: 235–282.[Medline]
42. Nicolaou, K. C., Pfefferkorn, J., Xu, J., Winssinger, N., Ohshima, T., Kim, S., Hosokawa, S., Vourloumis, D., van Delft, F. & Li, T. (1999) Total synthesis and chemical biology of the sarcodictyins. Chem. Pharm. Bull. (Tokyo) 47: 1199–1213.
43. Martin, A. B. & Schultz, P. G. (1999) Opportunities at the interface of chemistry and biology. Trends Cell Biol. 9: M24–M28.[Medline]
44. Perera, F. P. (1987) Molecular cancer epidemiology: a new tool in cancer prevention. J. Natl. Cancer Inst. 78: 887–898.
45. Schantz, S. P., Zhang, Z. F., Spitz, M. S., Sun, M. & Hsu, T. C. (1997) Genetic susceptibility to head and neck cancer: interaction between nutrition and mutagen sensitivity. Laryngoscope 107: 765–781.[Medline]
46. Groopman, J. D. & Kensler, T. W. (1999) The light at the end of the tunnel for chemical-specific biomarkers: daylight or headlight? Carcinogenesis 20: 1–11.
47. Vineis, P. & Porta, M. (1996) Causal thinking, biomarkers, and mechanisms of carcinogenesis. J. Clin. Epidemiol. 49: 951–956.[Medline]
48. Bardeesy, N., Falkoff, D., Petruzzi, M. J., Nowak, N., Zabel, B., Adam, M., Aguiar, M. C., Grundy, P., Shows, T. & Pelletier, J. (1994) Anaplastic Wilms' tumour, a subtype displaying poor prognosis, harbours p53 gene mutations. Nat. Genet. 7: 91–97.[Medline]
49. Wada, M., Bartram, C. R., Nakamura, H., Hachiya, M., Chen, D. L., Borenstein, J., Miller, C. W., Ludwig, L., Hansen-Hagge, T. E., Ludwig, W. D., Reiter, A., Mizoguchii, H. & Koeffler, H. P. (1993) Analysis of p53 mutations in a large series of lymphoid hematologic malignancies of childhood. Blood 82: 3163–3169.
50. Farmer, P. B. & Shuker, D. E. (1999) What is the significance of increases in background levels of carcinogen-derived protein and DNA adducts? Some considerations for incremental risk assessment. Mutat. Res. 424: 275–286.[Medline]
51. Hecht, S. S. (1999) Tobacco smoke carcinogens and lung cancer. J. Natl. Cancer Inst. 91: 1194–1210.
52. Lee, C. K., Brown, B. G., Reed, E. A., Coggins, C. R., Doolittle, D. J. & Hayes, A. W. (1993) Ninety-day inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette: DNA adducts and alveolar macrophage cytogenetics. Fundam. Appl. Toxicol. 20: 393–401.[Medline]
53. Wang, L. E., Bondy, M. L., de Andrade, M., Strom, S. S., Wang, X., Sigurdson, A., Spitz, M. R. & Wei, Q. (2000) Gender difference in smoking effect on chromosome sensitivity to gamma radiation in a healthy population. Radiat. Res. 154: 20–27.[Medline]
54. La, D. K. & Swenberg, J. A. (1996) DNA adducts: biological markers of exposure and potential applications to risk assessment. Mutat. Res. 365: 129–146.[Medline]
55. Dingley, K. H., Curtis, K. D., Nowell, S., Felton, J. S., Lang, N. P. & Turteltaub, K. W. (1999) DNA and protein adduct formation in the colon and blood of humans after exposure to a dietary-relevant dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Cancer Epidemiol. Biomarkers Prev. 8: 507–512.
56. Goldman, R. (2000) Quantitation of benzo[alpha]pyrene-DNA adducts by postlabeling with 14C-acetic anhydride and accelerator mass spectrometry. Chem. Biol. Interact. 126: 171–183.[Medline]
57. Harris, C. C. & Hollstein, M. (1993) Clinical implications of the p53 tumor-suppressor gene. N. Engl. J. Med. 329: 1318–1327.
58. Levine, A. J. (1997) p53, The cellular gatekeeper for growth and division. Cell 88: 323–331.[Medline]
59. Harris, C. C. (1996) Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies. J. Natl. Cancer Inst. 88: 1442–1455.
60. Greenblatt, M. S., Bennett, W. P., Hollstein, M. & Harris, C. C. (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 54: 4855–4878.
61. Hsu, I. C., Metcalf, R. A., Sun, T., Welsh, J. A., Wang, N. J. & Harris, C. C. (1991) Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350: 427–428.[Medline]
62. Bressac, B., Kew, M., Wands, J. & Ozturk, M. (1991) Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350: 429–431.[Medline]
63. Qian, G. S., Ross, R. K., Yu, M. C., Yuan, J. M., Gao, Y. T., Henderson, B. E., Wogan, G. N. & Groopman, J. D. (1994) A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People's Republic of China. Cancer Epidemiol. Biomarkers Prev. 3: 3–10.[Abstract]
64. Schatzkin, A. & Longnecker, M. P. (1994) Alcohol and breast cancer. Where are we now and where do we go from here? Cancer 74: 1101–1110.[Medline]
65. Longnecker, M. P., Newcomb, P. A., Mittendorf, R., Greenberg, E. R., Clapp, R. W., Bogdan, G. F., Baron, J., MacMahon, B. & Willett, W. C. (1995) Risk of breast cancer in relation to lifetime alcohol consumption. J. Natl. Cancer Inst. 87: 923–929.
66. Longnecker, M. P. (1994) Alcoholic beverage consumption in relation to risk of breast cancer: meta-analysis and review. Cancer Causes Control 5: 73–82.[Medline]
67. Harty, L. C., Caporaso, N. E., Hayes, R. B., Winn, D. M., Bravo-Otero, E., Blot, W. J., Kleinman, D. V., Brown, L. M., Armenian, H. K., Fraumeni, J. F., Jr. & Shields, P. G. (1997) Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers. J. Natl. Cancer Inst. 89: 1698–1705.[Abstract]
68. Freudenheim, J. L., Ambrosone, C. B., Moysich, K. B., Vena, J. E., Marshall, J. R., Graham, S., Laughlin, R., Nemoto, T. & Shields, P. G. (1997) Alcohol intake and breast cancer risk: effect of alcohol metabolism by alcohol dehydrogenase 3. Proc. Am. Assoc. Cancer Res. 38: 619 (abs.).
69. Ambrosone, C. B., Freudenheim, J. L., Thompson, P. A., Bowman, E., Vena, J. E., Marshall, J. R., Graham, S., Laughlin, R., Nemoto, T. & Shields, P. G. (1999) Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer. Cancer Res. 59: 602–606.
70. Wogan, G. N. (1992) Aflatoxins as risk factors for hepatocellular carcinoma in humans. Cancer Res. 52(suppl. 7): 2114S–2118S.
71. Denning, D. W., Allen, R., Wilkinson, A. P. & Morgan, M. R. (1990) Transplacental transfer of aflatoxin in humans. Carcinogenesis 11: 1033–1035.
72. Wild, C. P., Lu, S. H. & Montesano, R. (1987) Radioimmunoassay used to detect DNA alkylation adducts in tissues from populations at high risk for oesophageal and stomach cancer. IARC Sci. Publ. pp. 534–537.
73. Bosch, F. X. & Munoz, N. (1988) Prospects for epidemiological studies on hepatocellular cancer as a model for assessing viral and chemical interactions. IARC Sci. Publ. 89: 427–438.
74. Lunn, R. M., Zhang, Y. J., Wang, L. Y., Chen, C. J., Lee, P. H., Lee, C. S., Tsai, W. Y. & Santella, R. M. (1997) p53 Mutations, chronic hepatitis B virus infection, and aflatoxin exposure in hepatocellular carcinoma in Taiwan. Cancer Res. 57: 3471–3477.
75. Hatch, M. C., Chen, C. J., Levin, B., Ji, B. T., Yang, G. Y., Hsu, S. W., Wang, L. W., Hsieh, L. L. & Santella, R. M. (1993) Urinary aflatoxin levels, hepatitis-B virus infection and hepatocellular carcinoma in Taiwan. Int. J. Cancer 54: 931–934.[Medline]
76. Bulatao-Jayme, J., Almero, E. M., Castro, M. C., Jardeleza, M. T. & Salamat, L. A. (1982) A case-control dietary study of primary liver cancer risk from aflatoxin exposure. Int. J. Epidemiol. 11: 112–119.
77. Garner, R. C., Miller, E. C. & Miller, J. A. (1972) Liver microsomal metabolism of aflatoxin B1 to a reactive derivative toxic to Salmonella typhimurium TA 1530. Cancer Res. 32: 2058–2066.
78. Ueng, Y. F., Shimada, T., Yamazaki, H. & Guengerich, F. P. (1995) Oxidation of aflatoxin B1 by bacterial recombinant human cytochrome P450 enzymes. Chem. Res. Toxicol. 8: 218–225.[Medline]
79. Wang, H., Dick, R., Yin, H., Licad-Coles, E., Kroetz, D. L., Szklarz, G., Harlow, G., Halpert, J. R. & Correia, M. A. (1998) Structure-function relationships of human liver cytochromes P450 3A: aflatoxin B1 metabolism as a probe. Biochemistry 37: 12536–12545.[Medline]
80. Shimada, T. & Guengerich, F. P. (1989) Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver. Proc. Natl. Acad. Sci. U.S.A. 86: 462–465.
81. Reynolds, S. H., Stowers, S. J., Patterson, R. M., Maronpot, R. R., Aaronson, S. A. & Anderson, M. W. (1987) Activated oncogenes in B6C3F1 mouse liver tumors: implications for risk assessment. Science 237: 1309–1316.
82. Essigmann, J. M., Croy, R. G., Nadzan, A. M., Busby, W. F., Jr., Reinhold, V. N., Buchi, G. & Wogan, G. N. (1977) Structural identification of the major DNA adduct formed by aflatoxin B1 in vitro. Proc. Natl. Acad. Sci. U.S.A. 74: 1870–1874.
83. Iyer, R. S., Coles, B. F., Raney, K. D., Thier, R., Guengerich, F. P. & Harris, T. M. (1994) DNA adduction by the potent carcinogen aflatoxin B-1-mechanistic studies. J. Am. Chem. Soc. 116: 1603–1609.
84. Lilleberg, S. L., Cabonce, M. A., Raju, N. R., Wagner, L. M. & Kier, L. D. (1992) Alterations in the p53 tumor suppressor gene in rat liver tumors induced by aflatoxin B1. Prog. Clin. Biol. Res. 376: 203–222.[Medline]
85. Aguilar, F., Hussain, S. P. & Cerutti, P. (1993) Aflatoxin B1 induces the transversion of GT in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proc. Natl. Acad. Sci. U.S.A. 90: 8586–8590.
86. Mace, K., Aguilar, F., Wang, J. S., Vautravers, P., Gomez-Lechon, M., Gonzalea, F. J., Groopman, J., Harris, C. C. & Pfeifer, A. M. A. (1997) Aflatoxin B1 induced DNA adduct formation and p53 mutations in CYP450-expressing human liver cell lines. Carcinogenesis 18: 1291–1297.
87. Shimizu, Y., Zhu, J. J., Han, F., Ishikawa, T. & Oda, H. (1999) Different frequencies of p53 codon-249 hot-spot mutations in hepatocellular carcinomas in Jiang-su province of China. Int. J. Cancer 82: 187–190.[Medline]
88. Wogan, G. N. (1992) Molecular epidemiology in cancer risk assessment and prevention: recent progress and avenues for future research. Environ. Health Perspect. 98: 167–178.[Medline]
89. Wild, C. P., Jiang, Y. Z., Allen, S. J., Hall, A. J., Jansen, L. A. M. & Montesano, R. (1990) Aflatoxin-albumin adducts in human sera from different regions of the world. Carcinogenesis 11: 2271–2274.
90. Sun, Z., Lu, P., Gail, M. H., Pee, D., Zhang, Q., Ming, L., Wang, J., Wu, Y., Liu, G., Wu, Y. & Zhu, Y. (1999) Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. Hepatology 30: 379–383.[Medline]
91. Wang, J. S. & Groopman, J. D. (1999) DNA damage by mycotoxins. Mutat. Res. 424: 167–181.[Medline]
92. Bolton, M. G., Munoz, A., Jacobson, L. P., Groopman, J. D., Maxuitenko, Y. Y., Roebuck, B. D. & Kensler, T. W. (1993) Transient intervention with oltipraz protects against aflatoxin-induced hepatic tumorigenesis. Cancer Res. 53: 3499–3504.
93. Wang, J. S., Shen, X., He, X., Zhu, Y. R., Zhang, B. C., Wang, J. B., Qian, G. S., Kuang, S. Y., Zarba, A., Egner, P. A., Jacobson, L. P., Munoz, A., Helzlsouer, K. J., Groopman, J. D. & Kensler, T. W. (1999) Protective alterations in phase 1 and 2 metabolism of aflatoxin B1 by oltipraz in residents of Qidong, People's Republic of China. J. Natl. Cancer Inst. 91: 347–354.
94. International Agency for Research on Cancer. (1983) Benzo[a]pyrene. In: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, vol. 32, pp. 211–224. IARC, Lyon, France.
95. International Agency for Research on Cancer. (1985) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, pp. 7–271. IARC, Lyon, France.
96. Lioy, P. J. & Greenberg, A. (1990) Factors associated with human exposures to polycyclic aromatic hydrocarbons. Toxicol. Ind. Health 6: 209–223.[Medline]
97. Waldman, J. M., Lioy, P. J., Greenberg, A. & Butler, J. P. (1991) Analysis of human exposure to benzo(a)pyrene via inhalation and food ingestion in the Total Human Environmental Exposure Study (THEES). J. Expo. Anal. Environ. Epidemiol. 1: 193–225.[Medline]
98. Rothman, N., Poirier, M. C., Baser, M. E., Hansen, J. A., Gentile, C., Bowman, E. D. & Strickland, P. T. (1990) Formation of polycyclic aromatic hydrocarbon-DNA adducts in peripheral white blood cells during consumption of charcoal-broiled beef. Carcinogenesis 11: 1241–1243.
99. Rothman, N., Correa-Villasenor, A., Ford, D. P., Poirier, M. C., Haas, R., Hansen, J. A., O'Toole, T. & Strickland, P. T. (1993) Contribution of occupation and diet to white blood cell polycyclic aromatic hydrocarbon-DNA adducts in wildland firefighters. Cancer Epidemiol. Biomarkers Prev. 2: 341–347.[Abstract]
100. Benjamin, H., Storkson, J., Nagahara, A. & Pariza, M. W. (1991) Inhibition of benzo(a)pyrene-induced mouse forestomach neoplasia by dietary soy sauce. Cancer Res. 51: 2940–2942.
101. Weyand, E. H., Chen, Y. C., Wu, Y., Koganti, A., Dunsford, H. A. & Rodriguez, L. V. (1995) Differences in the tumorigenic activity of a pure hydrocarbon and a complex mixture following ingestion: benzo[a]pyrene vs manufactured gas plant residue. Chem. Res. Toxicol. 8: 949–954.[Medline]
102. Culp, S. J., Gaylor, D. W., Sheldon, W. G., Goldstein, L. S. & Beland, F. A. (1998) A comparison of the tumors induced by coal tar and benzo[a]pyrene in a 2-year bioassay. Carcinogenesis 19: 117–124.
103. Singh, S. V., Benson, P. J., Hu, X., Pal, A., Xia, H., Srivastava, S. K., Awasthi, S., Zaren, H. A., Orchard, J. L. & Awasthi, Y. C. (1998) Gender-related differences in susceptibility of A/J mouse to benzo[a]pyrene-induced pulmonary and forestomach tumorigenesis. Cancer Lett. 128: 197–204.[Medline]
104. Triolo, A. J., Aponte, G. E. & Herr, D. L. (1977) Induction of aryl hydrocarbon hydroxylase and forestomach tumors ben benzo(a)pyrene. Cancer Res. 37: 3018–3021.
105. Stoner, G. D., Greisiger, E. A., Schut, H. A., Pereira, M. A., Loeb, T. R., Klaunig, J. E. & Branstetter, D. G. (1984) A comparison of the lung adenoma response in strain A/J mice after intraperitoneal and oral administration of carcinogens. Toxicol. Appl. Pharmacol. 72: 313–323.[Medline]
106. Probst-Hensch, N. M., Sinha, R., Longnecker, M. P., Witte, J. S., Ingles, S. A., Frankl, H. D., Lee, E. R. & Haile, R. W. (1997) Meat preparation and colorectal adenomas in a large sigmoidoscopy-based case-control study in California (United States). Cancer Causes Control 8: 175–183.[Medline]
107. Giovannucci, E., Rimm, E. B., Stampfer, M. J., Colditz, G. A., Ascherio, A. & Willett, W. C. (1994) Intake of fat, meat, and fiber in relation to risk of colon cancer in men. Cancer Res. 54: 2390–2397.
108. Huggins, C. & Yang, N. C. (1962) Induction and extinction of mammary cancer. Science 137: 257–262.
109. Kotin, P., Falk, H. L. & Busser, R. (1959) Distribution, retention and elimination of c14–3,4-benzprene after administration to mice and rats. J. Natl. Cancer Inst. 23: 541–555.
110. Goldman, R., Bowman, E. D., Pellizzari, E. D., Beach, J. & Shields, P. G. (2000) Polycyclic aromatic hydrocarbons (PAH) in human lung, liver and breast tissue. Proc. Am. Assoc. Cancer Res. 41: 559–560.
111. Phillips, D. H. (1999) Polycyclic aromatic hydrocarbons in the diet. Mutat. Res. 443: 139–147.[Medline]
112. Buckley, T. J. & Lioy, P. J. (1992) An examination of the time course from human dietary exposure to polycyclic aromatic hydrocarbons to urinary elimination of 1-hydroxypyrene. Br. J. Ind. Med. 49: 113–124.[Medline]
113. Howard, J. W. & Fazio, T. (1980) Analytical methodology and reported findings of polycyclic aromatic hydrocarbons in foods. J. Assoc. Off. Anal. Chem. 63: 1077–1104.[Medline]
114. Sinha, R., Rothman, N., Brown, E. D., Mark, S. D., Hoover, R. N., Caporaso, N. E., Levander, O. A., Knize, M. G., Lang, N. P. & Kadlubar, F. F. (1994) Pan-fried meat containing high levels of heterocyclic aromatic amines but low levels of polycyclic aromatic hydrocarbons induces cytochrome P4501A2 activity in humans. Cancer Res. 54: 6154–6159.
115. Baghurst, K. (1999) Red meat consumption in Australia: intakes, contributions to nutrient intake and associated dietary patterns. Eur. J. Cancer Prev. 8: 185–191.[Medline]
116. Van Rooij, J. G., Veeger, M. M., Bodelier-Bade, M. M., Scheepers, P. T. & Jongeneelen, F. J. (1994) Smoking and dietary intake of polycyclic aromatic hydrocarbons as sources of interindividual variability in the baseline excretion of 1-hydroxypyrene in urine. Int. Arch. Occup. Environ. Health 66: 55–65.[Medline]
117. Cheng, S. C., Hilton, B. D., Roman, J. M. & Dipple, A. (1989) DNA adducts from carcinogenic and noncarcinogenic enantiomers of benzo[a]pyrene dihydrodiol epoxide. Chem. Res. Toxicol. 2: 334–340.[Medline]
118. Gelboin, H. V. (1980) Benzo[alpha]pyrene metabolism, activation and carcinogenesis: role and regulation of mixed-function oxidases and related enzymes. Physiol. Rev. 60: 1107–1166.
119. Pottenger, L. H., Christou, M. & Jefcoate, C. R. (1991) Purification and immunological characterization of a novel cytochrome P450 from C3H/10T1/2 cells. Arch. Biochem. Biophys. 286: 488–497.[Medline]
120. Shimada, T., Hayes, C. L., Yamazaki, H., Amin, S., Hecht, S. S., Guengerich, F. P. & Sutter, T. R. (1996) Activation of chemically diverse procarcinogens by human cytochrome P-450 1B1. Cancer Res. 56: 2979–2984.
121. Gupta, R. C., Reddy, M. V. & Randerath, K. (1982) 32P-postlabeling analysis of non-radioactive aromatic carcinogen–DNA adducts. Carcinogenesis 3: 1081–1092.
122. Alexandrov, K., Rojas, M., Geneste, O., Castegnaro, M., Camus, A. M., Petruzzelli, S., Giuntini, C. & Bartsch, H. (1992) An improved fluorometric assay for dosimetry of benzo(a)pyrene diol-epoxide-DNA adducts in smokers' lung: comparisons with total bulky adducts and aryl hydrocarbon hydroxylase activity. Cancer Res. 52: 6248–6253.
123. Bentsen-Farmen, R. K., Botnen, I. V., Noto, H., Jacob, J. & Ovrebo, S. (1999) Detection of polycyclic aromatic hydrocarbon metabolites by high-pressure liquid chromatography after purification on immunoaffinity columns in urine from occupationally exposed workers. Int. Arch. Occup. Environ. Health 72: 161–168.[Medline]
124. Godschalk, R. W., Ostertag, J. U., Moonen, E. J., Neumann, H. A., Kleinjans, J. C. & Van Schooten, F. J. (1998) Aromatic DNA adducts in human white blood cells and skin after dermal application of coal tar. Cancer Epidemiol. Biomarkers Prev. 7: 767–773.[Abstract]
125. Ryberg, D., Skaug, V., Hewer, A., Phillips, D. H., Harries, L. W., Wolf, C. R., Ogreid, D., Ulvik, A., Vu, P. & Haugen, A. (1997) Genotypes of glutathione transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk. Carcinogenesis 18: 1285–1289.
126. Wu, X., Shi, H., Jiang, H., Kemp, B., Hong, W. K., Delclos, G. L. & Spitz, M. R. (1997) Associations between cytochrome P4502E1 genotype, mutagen sensitivity, cigarette smoking and susceptibility to lung cancer. Carcinogenesis 18: 967–973.
127. Conney, A. H. (1982) Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture. Cancer Res. 42: 4875–4917.
128. Denissenko, M. F., Pao, A., Tang, M. & Pfeifer, G. P. (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science 274: 430–432.
129. Fiddler, W. (1975) The occurrence and determination of N-nitroso compounds. Toxicol. Appl. Pharmacol. 31: 352–360.[Medline]
130. Bartsch, H., O'Neill, I. & Schulte-Hermann, R. (eds.) (1987) The Relevance of N-Nitroso Compounds to Human Cancer. Exposures and Mechanisms. IARC Scientific Publications No. 84. International Agency for Research on Cancer, Lyon, France.
131. Wogan, G. N. & Tannenbaum, S. R. (1975) Environmental N-nitroso compounds: implications for public health. Toxicol. Appl. Pharmacol. 31: 375–383.[Medline]
132. Mirvish, S. S. (1995) Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett. 93: 17–48.[Medline]
133. Thor, H., Smith, M. T., Hartzell, P., Bellomo, G., Jewell, S. A. & Orrenius, S. (1982) The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes. A study of the implications of oxidative stress in intact cells. J. Biol. Chem. 257: 12419–12425.
134. Umbenhauer, D., Wild, C. P., Montesano, R., Saffhill, R., Boyle, J. M., Huh, N., Kirstein, U., Thomale, J., Rajewsky, M. F. & Lu, S. H. (1985) O6-methyldeoxyguanosine in oesophageal DNA among individuals at high risk of oesophageal cancer. Int. J. Cancer 36: 661–665.[Medline]
135. Bartsch, H. & Montesano, R. (1984) Relevance of nitrosamines to human cancer. Carcinogenesis 5: 1381–1393.
136. Idle, J. R. (1999) CYP2A6 polymorphism, nicotine, and environmental nitrosamines. Lancet 353: 2073.
137. Rogers, M. A., Vaughan, T. L., Davis, S. & Thomas, D. B. (1995) Consumption of nitrate, nitrite, and nitrosodimethylamine and the risk of upper aerodigestive tract cancer. Cancer Epidemiol. Biomarkers Prev. 4: 29–36.[Abstract]
138. De Stefani, E., Deneo-Pellegrini, H., Carzoglio, J. C., Ronco, A. & Mendilaharsu, M. (1996) Dietary nitrosodimethylamine and the risk of lung cancer: a case-control study from Uruguay. Cancer Epidemiol. Biomarkers Prev. 5: 679–682.
139. Bogovski, P. & Bogovski, S. (1981) Animal species in which N-nitroso compounds induce cancer. Int. J. Cancer 27: 471–474.[Medline]
140. Lijinsky, W. (1990) In vivo testing for carcinogenicity. In: Chemical Carcinogenesis and Mutagenesis I (Cooper, C. S. & Grover, P. L., eds.), pp. 179–209. Springer-Verlag, Berlin, Germany.
141. Shank, R. C. (1975) Toxicology of N-nitroso compounds. Toxicol. Appl. Pharmacol. 31: 361–368.[Medline]
142. Loeppky, R. N. (1999) The mechanism of bioactivation of N-nitrosodiethanolamine. Drug Metab. Rev. 31: 175–193.[Medline]
143. Lai, D. Y. & Arcos, J. C. (1980) Minireview: dialkylnitrosamine bioactivation and carcinogenesis. Life Sci. 27: 2149–2165.[Medline]
144. Lin, H. L., Parsels, L. A., Maybaum, J. & Hollenberg, P. F. (1999) N-nitrosodimethylamine-mediated cytotoxicity in a cell line expressing P450 2E1: evidence for apoptotic cell death. Toxicol. Appl. Pharmacol. 157: 117–124.[Medline]
145. Kamataki, T., Nunoya, K., Sakai, Y., Kushida, H. & Fujita, K. (1999) Genetic polymorphism of CYP2A6 in relation to cancer. Mutat. Res. 428: 125–130.[Medline]
146. Loveless, A. (1969) Possible relevance of O-6 alkylation of deoxyguanosine to the mutagenicity and carcinogenicity of nitrosamines and nitrosamides. Nature 223: 206–207.[Medline]
147. Goth, R. & Rajewsky, M. F. (1974) Persistence of O6-ethylguanine in rat-brain DNA: correlation with nervous system-specific carcinogenesis by ethylnitrosourea. Proc. Natl. Acad. Sci. U.S.A. 71: 639–643.
148. Singer, B. & Essigmann, J. M. (1991) Site-specific mutagenesis: retrospective and prospective. Carcinogenesis 12: 949–955.
149. Romach, E., Moore, J., Rummel, S. & Richie, E. (1994) Influence of sex and carcinogen treatment protocol on tumor latency and frequency of K-ras mutations in N-methyl-N-nitrosourea-induced lymphomas. Carcinogenesis 15: 2275–2280.
150. Lindahl, T. (1982) DNA repair enzymes. Annu. Rev. Biochem. 51: 61–87.[Medline]
151. Rydberg, B., Spurr, N. & Karran, P. (1990) cDNA cloning and chromosomal assignment of the human O6- methylguanine-DNA methyltransferase. cDNA expression in Escherichia coli and gene expression in human cells. J. Biol. Chem. 265: 9563–9569.
152. You, M., Wang, Y., Lineen, A. M., Gunning, W. T., Stoner, G. D. & Anderson, M. W. (1992) Mutagenesis of the K-ras protooncogene in mouse lung tumors induced by N-ethyl-N-nitrosourea or N-nitrosodiethylamine. Carcinogenesis 13: 1583–1586.
153. Cha, R. S., Thilly, W. G. & Zarbl, H. (1994) N-nitroso-N-methylurea-induced rat mammary tumors arise from cells with pre-existing oncogenic Ha-ras-1 gene mutations. Proc. Natl. Acad. Sci. U.S.A. 91: 3749–3753.
154. Nagata, Y., Abe, M., Kobayashi, K., Yoshida, K., Ishibashi, T., Naoe, T., Nakayama, E. & Shiku, H. (1990) Glycine to aspartic acid mutations at codon 13 of the c-Ki-ras gene in human gastrointestinal cancers. Cancer Res. 50: 480–482.
155. Skog, K. I., Johansson, M. A. & Jagerstad, M. I. (1998) Carcinogenic heterocyclic amines in model systems and cooked foods: a review on formation, occurrence and intake. Food Chem. Toxicol. 36: 879–896.[Medline]
156. Keating, G. A., Layton, D. W. & Felton, J. S. (1999) Factors determining dietary intakes of heterocyclic amines in cooked foods. Mutat. Res. 443: 149–156.[Medline]
157. Knize, M. G., Salmon, C. P., Pais, P. & Felton, J. S. (1999) Food heating and the formation of heterocyclic aromatic amine and polycyclic aromatic hydrocarbon mutagens/carcinogens. Adv. Exp. Med. Biol. 459: 179–193.[Medline]
158. Lynch, A. M., Knize, M. G., Boobis, A. R., Gooderham, N. J., Davies, D. S. & Murray, S. (1992) Intra-and interindividual variability in systemic exposure in humans to 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and 2-amino-1-methly-6-phenylimidazo[4,5-b]pyridine, carcinogens present in cooked beef. Cancer Res. 52: 6216–6223.
159. Butler, M. A., Guengerich, F. P. & Kadlubar, F. F. (1989) Metabolic oxidation of the carcinogens 4-aminobiphenyl and 4,4'-methylene-bis(2-chloroaniline) by human hepatic microsomes and by purified rat hepatic cytochrome P-450 monooxygenases. Cancer Res. 49: 25–31.
160. Lynch, A. M., Murray, S., Gooderham, N. J. & Boobis, A. R. (1995) Exposure to and activation of dietary heterocyclic amines in humans. Crit. Rev. Oncol. Hematol. 21: 19–31.[Medline]
161. Chen, J., Stampfer, M. J., Hough, H. L., Garcia-Closas, M., Willett, W. C., Hennekens, C. H., Kelsey, K. T. & Hunter, D. J. (1998) A prospective study of N-acetyltransferase genotype, red meat intake, and risk of colorectal cancer. Cancer Res. 58: 3307–3311.
162. Colvin, M. E., Hatch, F. T. & Felton, J. S. (1998) Chemical and biological factors affecting mutagen potency. Mutat. Res. 400: 479–492.[Medline]
163. Boobis, A. R., Lynch, A. M., Murray, S., de la Torre, R., Solans, A., Farre, M., Segura, J., Gooderham, N. J. & Davies, D. S. (1994) CYP1A2-catalyzed conversion of dietary heterocyclic amines to their proximate carcinogens is their major route of metabolism in humans. Cancer Res. 54: 89–94.
164. Schut, H. A. & Snyderwine, E. G. (1999) DNA adducts of heterocyclic amine food mutagens: implications for mutagenesis and carcinogenesis. Carcinogenesis 20: 353–368.
165. Yanagawa, Y., Sawada, M., Deguchi, T., Gonzalez, F. J. & Kamataki, T. (1994) Stable expression of human CYP1A2 and N-acetyltransferases in Chinese hamster CHL cells: mutagenic activation of 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. Cancer Res. 54: 3422–3427.
166. Lang, N. P., Butler, M. A., Massengill, J., Lawson, M., Stotts, R. C., Hauer-Jensen, M. & Kadlubar, F. F. (1994) Rapid metabolic phenotypes for acetyltransferase and cytochrome P4501A2 and putative exposure to food-borne heterocyclic amines increase the risk for colorectal cancer or polyps. Cancer Epidemiol. Biomarkers Prev. 3: 675–682.[Abstract]
167. Nowell, S. A., Massengill, J. S., Williams, S., Radominska-Pandya, A., Tephly, T. R., Cheng, Z., Strassburg, C. P., Tukey, R. H., MacLeod, S. L., Lang, N. P. & Kadlubar, F. F. (1999) Glucuronidation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine by human microsomal UDP-glucuronosyltransferases: identification of specific UGT1A family isoforms involved. Carcinogenesis 20: 1107–1114.
168. Ozawa, S., Tang, Y. M., Yamazoe, Y., Kato, R., Lang, N. P. & Kadlubar, F. F. (1998) Genetic polymorphisms in human liver phenol sulfotransferases involved in the bioactivation of N-hydroxy derivatives of carcinogenic arylamines and heterocyclic amines. Chem. Biol. Interact. 109: 237–248.[Medline]
169. Ji, H., Yu, M. C., Stillwell, W. G., Skipper, P. L., Ross, R. K., Henderson, B. E. & Tannenbaum, S. R. (1994) Urinary excretion of 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline in white, black, and Asian men in Los Angeles County. Cancer Epidemiol. Biomarkers Prev. 3: 407–411.[Abstract]
170. Reistad, R., Rossland, O. J., Latva-Kala, K. J., Rasmussen, T., Vikse, R., Becher, G. & Alexander, J. (1997) Heterocyclic aromatic amines in human urine following a fried meat meal. Food Chem. Toxicol. 35: 945–955.[Medline]
171. Kidd, L. C., Stillwell, W. G., Yu, M. C., Wishnok, J. S., Skipper, P. L., Ross, R. K., Henderson, B. E. & Tannenbaum, S. R. (1999) Urinary excretion of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in White, African-American, and Asian-American men in Los Angeles County. Cancer Epidemiol. Biomarkers Prev. 8: 439–445.
172. Friesen, M. D., Kaderlik, K., Lin, D., Garren, L., Bartsch, H., Lang, N. P. & Kadlubar, F. F. (1994) Analysis of DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in rat and human tissues by alkaline hydrolysis and gas chromatography/electron capture mass spectrometry: validation by comparison with 32P-postlabeling. Chem. Res. Toxicol. 7: 733–739.[Medline]
173. Totsuka, Y., Fukutome, K., Takahashi, M., Takahashi, S., Tada, A., Sugimura, T. & Wakabayashi, K. (1996) Presence of N2-(deoxyguanosin-8-yl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (dG-C8-MeIQx) in human tissues. Carcinogenesis 17: 1029–1034.
174. Zheng, W., Gustafson, D. R., Sinha, R., Cerhan, J. R., Moore, D., Hong, C. P., Anderson, K. E., Kushi, L. H., Sellers, T. A. & Folsom, A. R. (1998) Well-done meat intake and the risk of breast cancer. J. Natl. Cancer Inst. 90: 1724–1729.
175. Schiffman, M. H. & Felton, J. S. (1990) Re: Fried foods and the risk of colon cancer. Am. J. Epidemiol. 131: 376–378.
176. Ward, M. H., Sinha, R., Heineman, E. F., Rothman, N., Markin, R., Weisenburger, D. D., Correa, P. & Zahm, S. H. (1997) Risk of adenocarcinoma of the stomach and esophagus with meat cooking method and doneness preference. Int. J. Cancer 71: 14–19.[Medline]
177. Augustsson, K., Skog, K., Jagerstad, M., Dickman, P. W. & Steineck, G. (1999) Dietary heterocyclic amines and cancer of the colon, rectum, bladder, and kidney: a population-based study. Lancet 353: 703–707.[Medline]
178. Nagao, M. (1999) A new approach to risk estimation of food-borne carcinogens—heterocyclic amines—based on molecular information. Mutat. Res. 431: 3–12.[Medline]
179. Schwab, C. E., Huber, W. W., Parzefall, W., Hietsch, G., Kassie, F., Schulte-Hermann, R. & Knasmuller, S. (2000) Search for compounds that inhibit the genotoxic and carcinogenic effects of heterocyclic aromatic amines. Crit. Rev. Toxicol. 30: 1–69.[Medline]
180. Hammons, G. J., Fletcher, J. V., Stepps, K. R., Smith, E. A., Balentine, D. A., Harbowy, M. E. & Kadlubar, F. F. (1999) Effects of chemoprotective agents on the metabolic activation of the carcinogenic arylamines PhIP and 4-aminobiphenyl in human and rat liver microsomes. Nutr. Cancer 33: 46–52.[Medline]
181. Dashwood, R. H., Xu, M., Hernaez, J. F., Hasaniya, N., Youn, K. & Razzuk, A. (1999) Cancer chemopreventive mechanisms of tea against heterocyclic amine mutagens from cooked meat. Proc. Soc. Exp. Biol. Med. 220: 239–243.[Medline]
This article has been cited by other articles:
|
|
 |
|
  M. Najafzadeh, P. D. Reynolds, A. Baumgartner, and D. Anderson Flavonoids inhibit the genotoxicity of hydrogen peroxide (H2O2) and of the food mutagen 2-amino-3-methylimadazo[4,5-f]-quinoline (IQ) in lymphocytes from patients with inflammatory bowel disease (IBD) Mutagenesis, June 24, 2009; (2009) gep016v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Margaret Pratt, A. P. Reddy, J. D. Hendricks, C. Pereira, T. W. Kensler, and G. S. Bailey The importance of carcinogen dose in chemoprevention studies: quantitative interrelationships between, dibenzo[a,l]pyrene dose, chlorophyllin dose, target organ DNA adduct biomarkers and final tumor outcome Carcinogenesis, March 1, 2007; 28(3): 611 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Niture, C. S. Velu, Q. R. Smith, G.J. Bhat, and K. S. Srivenugopal Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines Carcinogenesis, February 1, 2007; 28(2): 378 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Shen, M. B. Terry, M. D. Gammon, M. M. Gaudet, S. L. Teitelbaum, S. M. Eng, S. K. Sagiv, A. I. Neugut, and R. M. Santella MGMT genotype modulates the associations between cigarette smoking, dietary antioxidants and breast cancer risk Carcinogenesis, December 1, 2005; 26(12): 2131 - 2137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M Battershill The Multiple Chemicals and Actions Model of carcinogenesis. A possible new approach to developing prevention strategies for environmental carcinogenesis Human and Experimental Toxicology, November 1, 2005; 24(11): 547 - 558. [Abstract] [PDF]
|
|
|
|
|
|
B. L. Pool-Zobel, V. Selvaraju, J. Sauer, T. Kautenburger, J. Kiefer, K. K. Richter, M. Soom, and S. Wolfl Butyrate may enhance toxicological defence in primary, adenoma and tumor human colon cells by favourably modulating expression of glutathione S-transferases genes, an approach in nutrigenomics Carcinogenesis, June 1, 2005; 26(6): 1064 - 1076. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. De Buck, P. Augustijns, and C. P. Muller Specific Antibody Modulates Absorptive Transport and Metabolic Activation of Benzo[a]pyrene across Caco-2 Monolayers J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 640 - 646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Murtaugh, C. Sweeney, K.-n. Ma, B. J. Caan, and M. L. Slattery The CYP1A1 Genotype May Alter the Association of Meat Consumption Patterns and Preparation with the Risk of Colorectal Cancer in Men and Women J. Nutr., February 1, 2005; 135(2): 179 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Potischman and J. L. Freudenheim Biomarkers of Nutritional Exposure and Nutritional Status: An Overview J. Nutr., March 1, 2003; 133(3): 873S - 874. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
