7,12-dimethylbenz[a]anthracene induces oxidative DNA modification in vivo

Krystyna Frenkel, Lihong Wei, Huachen Wei

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Initiation and promotion are major stages in the multistage carcinogenesis process. Formation of initiating carcinogen-DNA base adducts leads to heritable genetic changes, but the tumor-promoting events induced by complete carcinogens have not, as yet, been elucidated. Oxidant production and oxidative DNA damage induced by phorbol esters (i.e., 12-O-tetradecanoyl-phorbol-13-acetate) are associated with tumor promotion, while antioxidants and inhibitors of oxidative DNA damage suppress promotion and carcinogenesis. Our goal was to establish whether a carcinogen that requires oxidative metabolism for its activity can also induce oxidant production and DNA base oxidation. We found that topical treatment of SENCAR mice with 7,12-dimethylbenz[a]anthracene, which induces tumors in 40-50% of the mice, also causes hydrogen peroxide production and formation of oxidized bases (i.e., 8-hydroxyl-2'-deoxyguanosine and 5-hydroxymethyl-2'-deoxyuridine) in epidermal DNA. The levels of oxidized bases were of comparable magnitude to those mediated by the potent tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. The oxidized bases persisted over several weeks in epidermal DNA. These oxidative events appear to be temporally associated with inflammatory responses that include edema and polymorphonuclear leukocyte infiltration, which remained elevated over longer periods of time and at higher levels than those induced by phorbol ester. Because these processes are usually associated with tumor promotion, our results support the conjecture that oxidative events may be involved in what is operationally referred to as the tumor promotion process by 7,12-dimethylbenz[a]anthracene.

Original languageEnglish
Pages (from-to)373-380
Number of pages8
JournalFree Radical Biology and Medicine
Volume19
Issue number3
DOIs
StatePublished - Sep 1995
Externally publishedYes

Keywords

  • Carcinogenesis
  • Free radicals
  • Inflammation
  • Oxidative stress
  • Oxidized DNA bases
  • Polycyclic aromatic hydrocarbons
  • Tumor promotion

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