Journal Article

Carcinogen macromolecular adducts and their measurement

Miriam C. Poirier, Regina M. Santella and Ainsley Weston

in Carcinogenesis

Volume 21, issue 3, pages 353-359
Published in print March 2000 | ISSN: 0143-3334
Published online March 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.3.353
Carcinogen macromolecular adducts and their measurement

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Damage to DNA induced by carcinogenic chemicals reflects exposure and is directly related to tumor formation, whereas modification of protein provides relatively precise dosimetry for stable adducts of proteins with a known half-life. Sophisticated methods for the detection and quantitation of DNA and protein adducts have been developed during the last ~25 years. For DNA adducts the most widely used methods include electrochemical detection, mass spectrometry, fluorescence and phosphorescence spectroscopy, immunoassays and immunohistochemistry and 32P-post-labeling. Detection limits for quantitative assays are typically in the range of 1 adduct in 107 or 109 nucleotides. However, accelerator mass spectrometry, which is highly sophisticated but less accessible, has a detection limit of ~1 adduct in 1012 nucleotides. Methods for the determination of protein adducts include immunoassay and a variety of elegant high-resolution mass spectrometry approaches. The detection limit of ~0.1 fmol for protein adducts, is based primarily on method specificity and the availability of large quantities of sample material. Using these highly sensitive methods a major achievement has been the biomonitoring of chemically exposed human populations. Validation of macromolecular adduct formation in humans has been predicated on studies in animal models. Adduct formation in humans appears to be indicative of molecular dosimetry and suggestive of increased human cancer risk. However, despite the large body of literature documenting DNA and protein adduct molecular dosimetry for many carcinogen exposures, the relationship between adduct formation and human cancer risk has been defined for only a few carcinogens. Thus, elucidation of this association remains a compelling challenge. For the future, integration of DNA and protein adduct measurements together with documentation of correlative and subsequent events, and host susceptibility factors, within the context of valid molecular epidemiologic study designs, will further our understanding of human disease mechanisms.

Keywords: 4-ABP, 4-aminobiphenyl; AFB1, aflatoxin B1; AMS, accelerator mass spectrometry; B[a]P, benzo[a]pyrene; GC, gas chromatography; HBV, hepatitis B virus; HPLC, high performance liquid chromatography; MS, mass spectrometry; NNK, 4(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; PAH, polycyclic aromatic hydrocarbon; PHIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; RR, relative risk.

Journal Article.  6709 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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