Leukocyte DNA adducts after carcinogen exposure.
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 1994 Mar; :1-9
The potential use of leukocytes in circulation and in culture as exposure indicators, biomonitors of target tissue damage, and as predictors of risk of arylamine induced carcinogenesis was investigated. DNA of circulating mouse leukocytes formed adducts with metabolites of 2-aminofluorene (153786) (AF) following exposure to the carcinogen. These DNA adducts could be detected as soon as 3 hours after exposure. The concentration of leukocyte adducts declined in parallel with adducts in the liver, a target organ for arylamine carcinogenesis. DNA adducts in the urinary bladder also declined in an irregular course not correlated to the leukocyte decline. Chronic exposure for 7 days produced high amounts of leukocyte AF-DNA adducts. Studies indicated that the metabolism of AF and the formation of adducts in cultured mononuclear leukocytes (MNL) occurred in a time and dose dependent manner. A dependence of bladder DNA damage by AF in mice on the acetylation phenotype, the age at exposure, and the sex of the mice was found. Evidence was also reported for the formation of a bladder adduct by prostaglandin- synthase activation of AF. Cloned mouse N-acetyltransferases were expressed in COS-1 cells to determine the substrate specificity and other properties of the enzymes. The finding that both enzymes can acetylate the arylamine carcinogen AF means that DNA adduct formation is possible in any tissue having either isozyme of N- acetyltransferase. Thirty five tissues were examined for AF acetylating activity. In all tissues studied, except blood plasma and seminal vesicles, significant activity was noted. Among the higher levels of activity were those found in leukocytes. Mouse colon demonstrated the same genetic polymorphism in N-acetylation activity as reported for the liver, indicating that the inbred mouse may be a model for studies of human colon cancer which has been linked to N-acetylation phenotype.
NIOSH-Grant; Cancer; Laboratory-animals; Carcinogens; Blood-cells; DNA-adducts; Enzyme-activity; Arylamines
Pharmacology University of Michigan 6322 Medical Science I Bldg Ann Arbor, MI 48109-0626
Final Grant Report
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan
University of Michigan at Ann Arbor, Ann Arbor, Michigan