DNA adducts in model systems and humans.
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.
Turteltaub
K W
KW
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, CA 94550.
Frantz
C E
CE
Creek
M R
MR
Vogel
J S
JS
Shen
N
N
Fultz
E
E
D000588:Amines / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004032:Diet; D006801:Humans; D009369:Neoplasms / Q000209:etiology*
D000588:Amines; D002273:Carcinogens; D004273:DNA, Neoplasm