Preparation of the 8,9-epoxide of the mycotoxin aflatoxin B1:  the ultimate carcinogenic species

Baertschi, Steven W.; Raney, Kevin D.; Stone, Michael P.; Harris, Thomas M.

doi:10.1021/ja00231a083

Cited by 241 publications

(189 citation statements)

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“…Only the spectrum of the major diastereomer of AFB2-GA is discussed in detail including two-dimensional NMR spectra (see Supporting Information). A comparison of the chemical shifts and couplings constants of the proton signals of the two diastereomers of AFB2a (including Karplus analysis) [28,29] and AFB2-GA strongly suggests that the main isomer has an 8S configuration due to attack of glycolic acid on the aflatoxin's protonated enol ether group from the sterically less hindered side, as observed elsewhere [29,30] (note: the α/β nomenclature in [28] and [29] is not consistent). The NMR spectra of AFG2-GA are similar (not shown, see Supporting Information).…”

Section: Resultsmentioning

confidence: 96%

Novel Aflatoxin Derivatives and Protein Conjugates

et al. 2007

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Aflatoxins, a group of structurally related mycotoxins, are well known for their toxic and carcinogenic effects in humans and animals. Aflatoxin derivatives and protein conjugates are needed for diverse analytical applications. This work describes a reliable and fast synthesis of novel aflatoxin derivatives, purification by preparative HPLC and characterisation by ESI-MS and one-and two-dimensional NMR. Novel aflatoxin bovine serum albumin conjugates were prepared and characterised by UV absorption and MALDI-MS. These aflatoxin protein conjugates are potentially interesting as immunogens for the generation of aflatoxin selective antibodies with novel specificities.

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Section: Resultsmentioning

confidence: 96%

Novel Aflatoxin Derivatives and Protein Conjugates

et al. 2007

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“…AFB 1 is oxidized by cytochrome P450s to yield a variety of metabolites, and its toxicology has been reviewed (4). The major reactive metabolite is the exo-AFB 1 8,9-epoxide, which if not detoxified, can bind to double-stranded DNA to form the promutagenic AFB 1 -N 7 -guanine adduct or, following hydrolysis to the AFB 1 -dihydrodiol, with proteins such as albumin (5)(6)(7)(8). Both urinary AFB 1 -N 7 -guanine and serum AF-albumin levels are correlated with dietary intake of AFs (8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Quantitative Comparison of Aflatoxin B1 Serum Albumin Adducts in Humans by Isotope Dilution Mass Spectrometry and ELISA

Scholl

Turner

Sutcliffe

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Metabolic activation of the hepatocarcinogenic mycotoxin aflatoxin B 1 (AFB 1 ) results in the covalent attachment of AFB 1 to serum albumin. Digestion of adducted albumin releases AFB 1 -lysine, a biomarker of exposure status. AFalbumin adducts have been most frequently measured in precipitated serum albumin using an immunoassay (ELISA); however, a sensitive and specific isotope dilution mass spectrometric (IDMS) assay for measurement of AFB 1 -lysine in serum has recently been developed. The ELISA and IDMS methods were compared using 20 human sera collected in Guinea, West Africa, where AF exposure is endemic. Measurement of AFB 1 -lysine adduct concentrations by IDMS in serum and albumin precipitated from the same sample revealed that precipitation has no effect on the measured adduct levels. The concentration of AF-albumin adducts measured by ELISA and AFB 1 -lysine measured by IDMS in 2 mg of albumin were well correlated (R = 0.88, P < 0.0001); however, AF-albumin adduct concentrations measured by ELISA were on average 2.6-fold greater than those of the AFB 1 -lysine adduct. Although these data suggest that the ELISA is measuring other AF adducts in addition to AFB 1 -lysine, these biomarkers are comparable in their ability to assess AF exposure at AF-albumin concentrations z3 pg AFB 1 -lysine equivalents/mg albumin. Identification of other adducts may clarify the mechanistic basis for using AFprotein biomarkers to assess exposure status in future epidemiologic studies of liver cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(4):823 -6)

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“…AFB-lysine and 3 H-AFBlysine were synthesized from the reaction of 8,9-dihydro-8,9-dibromo-AFB or 8,9-dihydro-8,9-dibromo-3 H-AFB with N-␣-acetyl-L-lysine and purified by HPLC as described previously (25). AFB-N 7 -Gua and 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl formamido)-9-hydroxy-AFB (AFB-FAPyr) were synthesized by reaction of calf thymus DNA with chemically synthesized AFB-8,9-epoxide, which was prepared by the reaction of AFB with dimethyldioxirane as described by Baertschi et al (2). The oxidant dimethyldioxirane was synthesized as described by Murray and Jeyaraman (20) and Adam et al (1).…”

Section: Methodsmentioning

confidence: 99%

Development of Aflatoxin B ₁ -Lysine Adduct Monoclonal Antibody for Human Exposure Studies

Wang

Abubaker

et al. 2001

Appl Environ Microbiol

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Mouse monoclonal antibodies were developed against a synthetic aflatoxin B 1 (AFB)-lysine-cationized bovine serum albumin conjugate. The isotype of one of these antibodies, IIA4B3, has been classified as immunoglobulin G1(). The affinity and specificity of IIA4B3 were further characterized by a competitive radioimmunoassay. The affinities of IIA4B3 for AFB and its associated adducts and metabolites are ranked as follows: AFB-lysine > 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl formamido)-9-hydroxy-AFB > AFB ‫؍‬ 8,9-dihydro-8-(N 7 -guanyl)-9-hydroxy-AFB > aflatoxin M 1 > aflatoxin Q 1 . IIA4B3 had about a 10-fold higher affinity for binding to AFB-lysine adduct than to AFB when 3 H-AFB-lysine was used as the tracer. The concentration for 50% inhibition for AFB-lysine was 0.610 pmol; that for AFB was 6.85 pmol. IIA4B3 had affinities at least sevenfold and twofold higher than those of 2B11, a previously developed antibody against parent AFB, for the major aflatoxin-DNA adducts 8,9-dihydro-8-(N 7 -guanyl)-9-hydroxy-AFB and 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl formamido)-9-hydroxy-AFB, respectively. An analytical method based on a competitive radioimmunoassay with IIA4B3 and 3 H-AFB-lysine was validated with a limit of detection of 10 fmol of AFB-lysine adduct. The method has been applied to the measurement of AFB-albumin adduct levels in human serum samples collected from the residents of areas at high risk for liver cancer. Aflatoxins (AF), mainly produced by Aspergillus flavus andA. parasiticus, are a group of naturally occurring fungal metabolites that have long been recognized as significant environmental contaminants (17, 28). Aflatoxin B 1 (AFB), the most common mycotoxin found in human food and animal feed, is a potent hepatotoxic and genotoxic agent which has been listed as a known human carcinogen (group I) (6,17,28,29). Exposure to dietary AFB is one of the major risk factors in the etiology of human hepatocellular carcinoma in several regions of Africa and Southeast Asia (6,15,17,28,29,34). The development and application of highly sensitive and specific methods for detecting AFB and its associated metabolites and macromolecular adducts are critical for identifying individuals at high risk (13).The molecular biomarkers currently used in human and animal exposure studies are AFB metabolites and AFB macromolecular adducts, such as aflatoxin M 1 (AFM 1 ) and AFB-N 7 -guanine (AFB-N 7 -Gua), in urine and AFB-albumin adducts in serum (12,13,21,22,30). The use of AFB-albumin adducts as biomarkers is important because their estimated longer in vivo half-life compared to that of urinary metabolites may reflect integrated exposures over longer time periods (13,27). From a practical perspective pertinent to epidemiological studies, the measurement of serum AFB-albumin adduct levels offers a rapid, facile approach that can be used to screen very large numbers of people. Data from human exposure studies have also demonstrated that the excretion of urinary AFB-N 7 -Gua and the formatio...

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Preparation of the 8,9-epoxide of the mycotoxin aflatoxin B1: the ultimate carcinogenic species

Cited by 241 publications

References 2 publications

Novel Aflatoxin Derivatives and Protein Conjugates

Novel Aflatoxin Derivatives and Protein Conjugates

Quantitative Comparison of Aflatoxin B1 Serum Albumin Adducts in Humans by Isotope Dilution Mass Spectrometry and ELISA

Development of Aflatoxin B ₁ -Lysine Adduct Monoclonal Antibody for Human Exposure Studies

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Preparation of the 8,9-epoxide of the mycotoxin aflatoxin B1: the ultimate carcinogenic species

Cited by 241 publications

References 2 publications

Novel Aflatoxin Derivatives and Protein Conjugates

Novel Aflatoxin Derivatives and Protein Conjugates

Quantitative Comparison of Aflatoxin B1 Serum Albumin Adducts in Humans by Isotope Dilution Mass Spectrometry and ELISA

Development of Aflatoxin B 1 -Lysine Adduct Monoclonal Antibody for Human Exposure Studies

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Development of Aflatoxin B ₁ -Lysine Adduct Monoclonal Antibody for Human Exposure Studies