Excretion of an aflatoxin-guanine adduct in the urine of aflatoxin B1-treated rats

Cancer Research (Impact Factor: 9.33). 03/1981; 41(2):650-4.
Source: PubMed


Administration of aflatoxin B1 (AFB1) to rats resulted in the urinary excretion of 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1. This is the major product formed by the interaction in vivo of AFB1 with rat liver nucleic acids. The adduct was isolated from urine by the combined use of preparative and analytical high-pressure liquid chromatography and was quantitated by measurement of absorbance at 365 nm. The method allowed reproducible quantitation of adduct in urine samples from rats treated with AFB1 by i.p. injection at levels as low as 0.125 mg/kg. Application of the method to urine samples from rats given injections of AFB1 (1 mg/kg) revealed the presence of a compound chromatographically identical to authentic 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1. Spectral and chemical analysis of microgram quantities of this compound provided strong evidence that this compound is identical to authentic adduct. Measurement of this adduct in the urine of rats given injections of different doses of AFB1 showed that excretion occurs in a dose-dependent manner. Comparison of the dose-response curve for adduct excretion with that previously observed for adduct formation in rat liver DNA in vivo revealed a high degree of qualitative similarity, with the levels of adduct excreted in urine representing 30 to 40% of the levels seen initially in liver DNA.

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    • "The epoxide can react further by interacting with DNA to produce a promutagenic aflatoxin- N7-guanine adduct. This adduct is unstable in DNA, rapidly undergoes depurination, and is excreted in urine (Bennett et al., 1981). The epoxide can also form products that react with serum albumin to form long-lived lysine adducts (Sabbioni et al., 1987). "
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    ABSTRACT: The identification of aflatoxins as human carcinogens has stimulated extensive research efforts, which continue to the present, to assess potential health hazards resulting from contamination of the human food supply and to minimize exposure. The use of biomarkers that are mechanistically supported by toxicological studies will be important tools for identifying stages in the progression of development of the health effects of environmental agents. miRNAs are small non-coding mRNAs that regulate post-transcriptional gene expression. Also, they are molecular markers of cellular responses to various chemical agents. Growing evidence has demonstrated that environmental chemicals can induce changes in miRNA expression. miRNAs are good biomarkers because they are well defined, chemically uniform, restricted to a manageable number of species, and stable in cells and in the circulation. miRNAs have been used as serological markers of HCC and other tumors. The expression patterns of different miRNAs can distinguish among HCC-hepatitis viruses related, HCC cirrhosis-derivate, and HCC unrelated to either of them. The main objective of this review is to find unreported miRNAs in HCC related to other causes, so that they can be used as specific molecular biomarkers in populations exposed to aflatoxins and as early markers of exposure, damage/presence of HCC. Until today specific miRNAs as markers for aflatoxins-exposure and their reliability are currently lacking. Based on their elucidated mechanisms of action, potential miRNAs that could serve as possible markers of HCC by exposure to aflatoxins are miR-27a, miR-27b, miR-122, miR-148, miR-155, miR-192, miR-214, miR-221, miR-429, and miR-500. Future validation for all of these miRNAs will be needed to assess their prognostic significance and confirm their relationship with the induction of HCC due to aflatoxin exposure.
    Full-text · Article · Mar 2014 · Frontiers in Microbiology
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    • "The epoxide can react further by interacting with DNA to produce a promutagenic aflatoxin-N 7 -guanine adduct . This adduct is unstable in DNA , rapidly undergoes depurination , and is excreted in urine ( Bennett et al., 1981 ). The epoxide can also form products that react with serum albumin to form long - lived lysine adducts ( Sabbioni et al . "
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    ABSTRACT: Since their discovery 50 years ago, the aflatoxins have become recognized as ubiquitous contaminants of the human food supply throughout the economically developing world. The adverse toxicological consequences of these compounds in populations are quite varied because of a wide range of exposures leading to acute effects, including rapid death, and chronic outcomes such as hepatocellular carcinoma. Furthermore, emerging studies describe a variety of general adverse health effects associated with aflatoxin, such as impaired growth in children. Aflatoxin exposures have also been demonstrated to multiplicatively increase the risk of liver cancer in people chronically infected with hepatitis B virus (HBV) illustrating the deleterious impact that even low toxin levels in the diet can pose for human health. The public health impact of aflatoxin exposure is pervasive. Aflatoxin biomarkers of internal and biologically effective doses have been integral to the establishment of the etiologic role of this toxin in human disease through better estimates of exposure, expanded knowledge of the mechanisms of disease pathogenesis, and as tools for implementing and evaluating preventive interventions.
    Full-text · Article · Sep 2010 · Toxicological Sciences
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    • "The chemical structures of the major aflatoxin epoxide derived macromolecular adducts have been identified (Essigmann et al. 1977; Sabbioni et al. 1987). Interest in using the major aflatoxin – nucleic acid adduct in urine as a biomarker was enhanced by the finding that this metabolite is excreted exclusively in urine of rats exposed to AFB 1 (Bennett et al. 1981). This finding obviates the potential pharmacokinetic problem of biliary and urinary excretion. "
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    ABSTRACT: Over the past 30 years there have been extensive efforts to investigate the association between aflatoxin exposure and human liver cancer. These studies have been hindered by the lack of adequate dosimetry data on aflatoxin intake, excretion, and metabolism in people, as well as by the general poor quality of worldwide cancer morbidity and mortality statistics. These realities have spurred the efforts to develop new technologies to assess exposure status and risk for aflatoxins, and these agents are among the few environmental carcinogens for which quantitative risk assessments have been attempted. One of the goals of these risk assessments has been the development of primary and secondary preventive intervention methods to lower the human health impact from aflatoxin exposures. The long-term goal of the research described herein is the application of biomarkers to the development of preventive interventions for use in human populations at high risk for cancer. Several of the aflatoxin-specific biomarkers have been validated in epidemiologic studies and are now available for use as intermediate biomarkers in prevention trials. The development of these aflatoxin biomarkers has been based upon the knowledge of the biochemistry and toxicology of aflatoxins gleaned from both experimental and human studies. These biomarkers have been utilized subsequently in experimental models to provide data on the modulation of the markers under different situations of disease risk. This systematic approach provides encouragement for preventive interventions and should serve as a template for the development for the development and validation of other chemical-specific biomarkers and their application to cancer or other chronic diseases.
    Full-text · Article · Mar 1996 · Canadian Journal of Physiology and Pharmacology
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