Analysis of point mutations in murine c-Ha-ras of skin tumors initiated with dibenz[a,j]anthracene and derivatives

✍ Scribed by Rosalynn D. Gill; Linda Beltrán; Anusha N. Nettikumara; Ronald G. Harvey; Arend Kootstra; John Digiovanni

• Publisher: John Wiley and Sons
• Year: 1992
• Tongue: English
• Weight: 737 KB
• Volume: 6
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/mc.2940060109

✦ Synopsis

Abstract

This study was designed to evaluate the point mutations in the murine c‐Ha‐ras gene of skin papillomas induced by initiation with dibenz[a,j]anthracene(DB[a,j]A), its bay‐region anti‐diol epoxide ((± anti‐DB[a,j]A‐DE), and a 7,14‐dimethyl analogue (7,14‐diMeDB[a,j]A). Recent studies (Nair RV, et al., Chem Res Toxicol 4:115–122, 1991) in our laboratory have revealed both deoxyguanosine (dGuo) and deoxyadenosine (dAdo) adducts formed from the anti‐ and syn‐diol epoxides of DB[a,j]A in cultured mouse epidermal cells after exposure to this hydrocarbon. Using PCR amplification and direct sequencing, we found specific A^182^±T transversion mutations (eight of 10 tumors) in codon 61 of c‐Ha‐ras in papillomas induced by initiation with DB[a,j]A. Analysis of papillomas generated by initiation with the more biologically potent analogue 7,14‐diMeDB[a,j]A revealed that five of five tumors exhibited A^182^±T transversions in codon 61. The nature of the changes in the two DB[a,j]A tumors not showing codon 61 mutations in Ha‐ras is currently not known since these tumor DNAs also did not possess c‐Ha‐ras mutations at codons 12,13, or 59. Interestingly, papillomas produced by initiation with (±)anti‐DB[a,j]A‐DE also possessed A^182^±T transversion mutations in codon 61 of c‐Ha‐ras (five of five tumors). These data suggest that dAdo adducts derived from both parent hydrocarbons may play an important role in their tumor‐initiating activity and possibly implicate a specific diol epoxide‐dAdo adduct in this process. © 1992 Wiley‐Liss, Inc.