Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas: the role of apurinic sites.

Abstract

Mouse skin tumors contain activated c-H-ras oncogenes, often caused by point mutations at codons 12 and 13 in exon 1 and codons 59 and 61 in exon 2. Mutagenesis by the noncoding apurinic sites can produce G -* T and A --T transversions by DNA misreplication with more frequent insertion of deoxyadenosine opposite the apurinic site. Papillomas were induced in mouse skin by several aromatic hydrocarbons, and mutations in the c-H-ras gene were determined to elucidate the relationship among DNA adducts, apurinic sites, and ras oncogene mutations. Dibenzo-[a,l pyrene (DB[a,l]P), DB [a,l]P-11,12-dihydrodiol, anti-DB[a,l]P-11,12-diol-13,14-epoxide, DB[a,l]P-8,9-dihydrodiol, 7,12-dimethylbenz [a] anthracene (DMBA), and 1,2,3,4-tetrahydro-DMBA consistently induced a CAA -> CTA mutation in codon 61 of the c-H-ras oncogene. Benzo[a]pyrene induced a GGC -* GTC mutation in codon 13 in 54% of tumors and a CAA -> CTA mutation in codon 61 in 15%. The pattern of mutations induced by each hydrocarbon correlated with its profile of DNA adducts. For example, both DB[a,l]P and DMBA primarily form DNA adducts at the N-3 and/or N-7 of deoxyadenosine that are lost from the DNA by depurination, generating apurinic sites. Thus, these results support the hypothesis that misreplication of unrepaired apurinic sites generated by loss of hydrocarbon-DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin.The ras family of oncogenes includes the closely related H-, Kirsten-, and N-ras genes.

Cigarette smoke condensate-induced level of adenomatous polyposis coli blocks long-patch base excision repair in breast epithelial cells

“…CSC, B[a]P, and other constituents of CSC have been shown to generate abasic DNA damage in cells (Chakravarti et al, 1995;DeMarini et al, 1995;Cavlieri and Rogan, 1998). However, the mechanism by which they are repaired is not yet well described.…”

“…Those adducts that are repaired by the BER pathway, can be either stable or depurinating. Through comprehensive studies of the DNA adducts of B[a]P, Cavalieri and Rogan (1998) and Chakravarti et al (1995) have demonstrated a strong association between depurinating adducts and oncogenic mutations in the H-ras gene, suggesting that these adducts are important in tumor initiation and progression. Furthermore, it has been found that in lung cancer cells, approximately 30% of GC to TA transversions occur at the hot spot codon 248 and 273 of TP53 gene and at codon 12, 13 or 61 of K-ras gene (Slebos et al, 1991;Husgafvel-Pursiainen et al, 1993;Westra et al, 1993;Greenblatt et al, 1994).…”

“…The B[a]P-induced apurinic sites in cellular DNA are 15-to 120-fold higher than those formed spontaneously, suggesting that this large increase in apurinic sites has the potential of overwhelming the cell repair capacity before replication occurs (Chakravarti et al, 1995;Cavlieri and Rogan, 1998). Thus, it is likely that nonrepair of apurinic sites in the DNA induced by carcinogenic constituents of CSC may generate critical mutations which in turn play a role in initiating transformation of normal breast epithelial cells; however, the mechanisms remain obscure.…”

Prostate cancer risk from occupational exposure to polycyclic aromatic hydrocarbons interacting with the GSTP1 Ile105Val polymorphism

“…PAH are ubiquitous environmental contaminants that result from incomplete combustion processes and are known carcinogens [8]. PAH are thought to exert their carcinogenic properties through their ability to form PAH-DNA adducts [9][10][11]. Both casecontrol [12] and cohort [13] studies have found that most jobs associated with occupational PAH exposure have the potential for prostate cancer.…”

Formation of 8-Oxo-7,8-dihydro-2‘-deoxyguanosine (8-Oxo-dGuo) by PAH o-Quinones: Involvement of Reactive Oxygen Species and Copper(II)/Copper(I) Redox Cycling

“…For example, the BP radical cation can yield N7 and C8 depurinating adducts with guanine and adenine that have resulted in H-ras mutation in mouse skin (9,10). (±)-Anti-BP-7,8-diol-9,10-epoxide a representative diol-epoxide can form stable N 2 -adducts with 2′-deoxyguanosine in vivo and in vitro (11)(12)(13)(14) and leads to the mutation of p53 and H-ras (3,15).…”