7
Views
20
CrossRef citations to date
0
Altmetric
Part two: Carcinogenesis at the molecular level

Binding of polycyclic aromatic hydrocarbons to DNA: Comparison with mutagenesis and tumorigenesis

, &
Pages 1009-1020 | Published online: 20 Oct 2009
 

Abstract

Although the necessity for metabolic activation of chemical carcinogens is well established, the critical target(s) for their action is not known. Many recent investigations have been based on the assumption that carcinogens act through somatic mutation and have focused on carcinogen‐nucleic acid interactions. Methods have been developed for detecting biological consequences of DNA damage caused by carcinogenic metabolites (for example, mutagenesis in prokaryotes or eukaryotes) or quantitating specific metabolite‐DNA adducts. Such methods have made it possible to elucidate probable ultimate carcinogenic forms and study cellular factors affecting carcinogen‐DNA interactions. It has been shown that numerous reactive metabolites of, for example, benzo[a] pyrene generated by microsomes are capable of binding to exogenous DNA in vitro, but in isolated organs or in cells and intact tissues most of these reactive forms are detoxified or otherwise “trapped” before they reach nuclear DNA. After binding, DNA repair mechanisms can also remove damaged bases. Binding of carcinogens to DNA affects the structure and function of the DNA, causing local denaturations and impaired transcription, but the significance of these findings in vivo is unclear.

Because chemical carcinogenesis is a multistep process, a direct link between DNA binding and the final outcome, manifest cancer, is difficult to establish. Excellent correlations between mutagenesis, malignant transformation, and carcinogenesis may merely reflect the fact that the production of reactive intermediates is required for all these phenomena. Recent studies measuring “true” instead of “total” binding of carcinogens to DNA have yielded better correlations with mutagenesis and carcinogenesis. Nevertheless, much more must be known about the oncogenic process before it can be decided whether DNA is really the critical target for carcinogens and somatic mutation the initial step in the oncogenic process.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.