Marc J. Mass1, Jeffrey A. Ross1, Stephen Nesnow1, Anita J. Jeffers2, Garret B. Nelson2, Anthony J. Galati3,4, Gary D. Stoner3,4
1Carcinogenesis and Metabolism Branch, Genetic Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina
2EHRT, Inc., Research Triangle Park, North Carolina
3Department of Pathology, Medical College of Ohio, Toledo, Ohio
4Department of Preventive Medicine, Arthur James Cancer Hospital, Ohio State University, Columbus, Ohio
Tóm tắt
AbstractStrain A/J mice received intraperitoneal injections of benz[j]aceanthrylene (B[j]A) or benzo[a]pyrene (B[a]P). At 24, 48, and 72 h, lung tissues were removed for analysis of B[a]P‐ or B[j]A‐derived DNA adduct formation during the first 3 d of exposure. One group of mice exposed to these hydrocarbons was kept for 8 mo to determine lung tumor multiplicity, the occurrence of mutations in codons 12 and 61 of the Ki‐ras gene in the tumors that arose, the relationship between Ki‐ras oncogene mutations in tumors, and the presence and quantity of genomic DNA adducts. The major DNA adduct in the lungs of mice exposed to B[a]P was N2‐(10β‐[ + B,7α, 9α‐trihydroxy‐7,8,9,10‐tetrahydrobenzo[a]pyrene]yl)‐deoxyguanosine (BPDE‐l‐dGuo) arising from bay‐region diolepoxide activation of B[a]P and was consistent with the occurrence of tumors with mutations GGT → TGT (56%), GGT → GTT (25%), and GGT → GAT (19%) in codon 12, all involving mutations of a guanine. B[j]A, a demethylated analogue of 3‐methylcholanthrene (3‐MCA) with an unsaturated cyclopenta ring, produced 16‐ to 60‐fold more tumors at equivalent doses than did B[a]P; the mutations in tumors were GGT → TGT (4%), GGT → GTT (30%), and GGT → CGT (65%). Analysis of adduction patterns in DNA suggested that B[j]A was activated to form DNA‐binding derivatives in A/J mouse lungs primarily at the cyclopenta ring even though B[j]A contains a bay region. As reported in the published literature, the mutation spectrum induced by 3‐MCA in Ki‐ras codon 12 of mouse cells is similar to that of B[a]P but not to that of its close relative B[j]A. In contrast to B[j]A, 3‐MCA is activated mostly via a bay‐region diol‐epoxide since its cyclopenta ring is saturated and not easily epoxidated. Therefore, we propose that the GGT → CGT mutations produced by B[j]A in Ki‐ras codon 12 were mostly the result of cyclopentaring‐derived adducts.
