DNA adducts in model systems and humans

Abstract

The etiology of chemically induced cancer is thought to involve the covalent binding of carcinogens to DNA (adducts) leading to mutations in oncogenes or tumor suppressor genes, and ultimately to tumors. Thus, the DNA-carcinogen adduct has been used as a measurable biochemical endpoint in laboratory studies designed to assess carcinogen exposure, carcinogen metabolism, mutagenesis, and tumorigenesis. Unfortunately, the significance of adducts in the etiology of human cancer is still unclear. This is partially due to the difficulty detecting adducts at carcinogen exposures relevant to humans, which are often orders of magnitude lower than animal model exposures. The relationship between adducts and higher biological effects is also not known at low doses. We have been assessing the DNA damage caused by exposure to heterocyclic amine carcinogens in the diet.Using the technique of 32P-postlabeling in combination with accelerator mass spectrometry, we have determined that DNA adduction in rodents decreases linearly with decreasing dose from the high doses used in typical cancer bioassays to the low doses relevant to human exposures. For a given tissue, adduct levels are correlated with dose, but the level of DNA modification by carcinogens is tissue-specific and does not completely correlate with tumor site. This lack of correlation may be due to differences in adduct formation and repair rates among tissues. Comparison of carcinogen metabolism routes between rodents and humans also indicates that species differences could influence the amount and type of damage resulting from exposure to these carcinogens. The use of model systems to study dosimetry, species differences in adduction, and role of adducts in mutation will ultimately lead to a better understanding of the significance of adducts in human disease. This should eventually allow the use of adducts as biomarkers for estimating carcinogen exposure and individual SuScePtibilitY. We have used a number of models, including whole animals, tissue fractions, and bacterial assays, to study the mechanisms leading to DNA adduct formation, species differences in these mechanisms, and the dosimetry of DNA adduction. In particular, we have examined a group of dietary heterocyclic amine carcinogens that may be causative factors in the incidence of human colon cancer [a]. We have principally used the techniques of accelerator mass spectrometry (AMS) and "P-postlabeling. AMS is a low-energy nuclear physics technique for measuring isotopes, making it ideal for isotope tracer studies [3]; it isolates and counts specific nuclei particle by particle as opposed to measuring atomic decay. Depending on the isotope, AMS gives a lo3-to lO6-fold improvement in isotope detection efficiency relative to decay counting, allowing us to quantitatively measure DNA adduct levels on the order of one adduct per 1011-1012 nucleotides (1 adduct/100-1000 cells) [3,4]. This sensitivity has made possible studies on DNA adduction at doses of chemical carcinogens close to actual human exposur...

Promoting Effect of a High-Fat/High-Protein Diet in DMBA-Induced Ductal Pancreatic Cancer in Rats

“…7 DNA adduct formation of carcinogens can lead to mutations in oncogenes and tumor suppressor genes. 8 Carcinogen DNA adducts have been found in human and rat organs, and increased levels of aromatic and lipid peroxidation-related DNA adducts in pancreas adjacent to cancers in human tissues are consistent with a pathogenetic role of DNA adducts in pancreatic cancer. 9 Interactions of carcinogens with DNA can be altered by dietary and environmental factors.…”

The treatment of Chagas disease patients with nitroderivative is unsatisfactory

“…In contrast, malignant neoplasia was neither seen in the T. cruzi-infected rabbits nor in uninfected, control rabbits. The etiology of chemically induced cancer may involve the covalent binding of the carcinogen to DNA (adducts) leading to mutation in oncogenes or tumor suppressor genes, and ultimately to tumors 17,30,44,45,47 . These formed adducts have the potential to bind covalently to DNA and induce oxidative damage to DNA.…”

“…These formed adducts have the potential to bind covalently to DNA and induce oxidative damage to DNA. Thus growth transformation has been measured by DNA-carcinogen adducts formed by exposure to carcinogenic nitroderivative compounds in model systems and in humans 37,45,47 . Figure 1A shows a malignant type non-Hodgkin lymphoma that invades the kidney of a benznidazole treated rabbit.…”

“…Severe cytotoxicity has been described for several nitroderivatives, and, in recent decades, these compounds have been shown to possess a variable degree of mutagenic, teratogenic, carcinogenic and sterilizing activities 4,5,16,17,27,30,37,44,45,47 . Cytotoxicity and genotoxicity associated with nitroderivatives seem to depend on the binding of electrophilic radicals to macromolecules and DNA, after enzymatic reduction of the nitro-group and generation of free electrophilic radicals, such as nitro-anions, hydroxyl, singlet oxygen and hydrogen peroxide 18,21,30,31,41 .…”

Determination of 2-Amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) and Its Metabolite 2-Hydroxyamino-PhIP by Liquid Chromatography/Electrospray Ionization–Ion Trap Mass Spectrometry

“…Most of these methods have been devoted to the determination of the conjugated metabolites of PhIP. Accelerator mass spectrometry using [ 14 C]PhIP has been extensively used for the analysis of PhIP metabolites and PhIP-DNA adducts in rodents as well as in humans (25)(26)(27)(28)(29). Although the method is very sensitive, it requires the synthesis of radioactive compounds, very expensive instrumentation, and an elaborate setup.…”