Carcinogenesis Advance Access published online on October 25, 2009
Carcinogenesis, doi:10.1093/carcin/bgp252
Basic properties and molecular mechanisms of exogenous chemical carcinogens
a Cancer Research Center, Association for Research and Treatments Against Cancer (ARTAC), F-75015 Paris, France
b Paris Descartes University and Department of Medical Oncology, European Hospital Georges Pompidou (HEGP), F-75015 Paris, France
* Corresponding author: P. Irigaray, PhD, ARTAC, 57-59 rue de la convention, 75015 Paris, Phone: +33 (0)1 45 78 53 53, Fax: +33 (0)1 45 78 53 50, E-mail: philippei.artac{at}gmail.com
Exogenous chemical carcinogenesis is an extremely complex multifactorial process during which gene-environment interactions involving chronic exposure to exogenous chemical carcinogens (ECCs) and polymorphisms of cancer susceptibility genes add further complexity. We describe the properties and molecular mechanisms of ECCs that contribute to induce and generate cancer. A basic and specific property of many lipophilic organic ECCs including polycyclic aromatic hydrocarbons and polyhalogenated aromatic hydrocarbons is their ability to bioaccumulate in the adipose tissue, from where they may be released in the blood circulation and target peripheral tissues for carcinogenesis. Many organic ECCs are procarcinogens and consequently need to be activated by the cytochrome P450 (CYP) system and/or other enzymes before they can adduct DNA and proteins. Because they contribute not only to the cocarcinogenic and promoting effects of many aromatic pollutants, but also to their mutagenic effects, the aryl hydrocarbon receptor (AhR)-activating and the inducible CYP systems are central to exogenous chemical carcinogenesis. Another basic property of ECCs is their ability to induce stable and bulky DNA adducts which cannot be simply repaired by the different repair systems. In addition, following ECC exposure mutagenesis may also be caused indirectly by free radical production and by epigenetic alterations. As a result of complex molecular interplays, direct and/or indirect mutagenesis may especially account for the carcinogenic effects of many exogenous metals and metalloids. Because of these molecular properties and action mechanisms, we conclude that ECCs could be major contributors to human cancer, with obviously great public health consequences.
Key Words: Cancer • Carcinogenesis • Cocarcinogens • Chemical Carcinogens • Dioxins • Environmental Pollutants • Free Radicals • Genetic Polymorphisms • Initiation • Metals • Mutagens • Mutations • PAHs • PCBs • Promotion • Tobacco Smoking • Xenobiotics
Received February 12, 2009; revised September 28, 2009; accepted October 12, 2009.