KI-RAS ONCOGENE MUTATIONS IN TUMORS AND DNA-ADDUCTS FORMED BY BENZ[J]ACEANTHRYLENE AND BENZO[A]PYRENE IN THE LUNGS OF STRAIN A J MICE/

Strain A/J mice received intraperitoneal injections of benz[j]aceanthr ylene (B[j]A) or benzo[a]pyrene (B[a]P). At 24, 48, and 72 h, lung tis sues were removed for analysis of B[a]P- or B[j]A-derived DNA adduct f ormation during the first 3 d of exposure. One group of mice exposed t o these hydrocarbons was kept for 8 mo to determine lung tumor multipl icity, the occurrence of mutations in codons 12 and 61 of the Ki-ras g ene in the tumors that arose, the relationship between Ki-ras oncogene mutations in tumors, and the presence and quantity of genomic DNA add ucts. The major DNA adduct in the lungs of mice exposed to B[a]P was N 2-(10beta-[+B,7alpha, 8,9,10-tetrahydrobenzo[a]pyrene]yl)-deoxyguanosi ne (BPDE-I-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 in volving mutations of a guanine. B[j]A, a demethylated analogue of 3-me thylcholanthrene (3-MCA) with an unsaturated cyclopenta ring, produced 16-to 60-fold more tumors at equivalent doses than did B[a]P; the mut ations 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 a ctivated 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 rep orted 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 i s activated mostly via a bay-region diol-epoxide since its cyclopenta ring is saturated and not easily epoxidated. Therefore, we propose tha t the GGT-->CGT mutations produced by B[j]A in Ki-ras codon 12 were mo stly the result of cyclopentaring-derived adducts. (C) 1993 Wiley-Liss , Inc.