Carcinogenic polycyclic aromatic hydrocarbon‐DNA adducts and mechanism of action

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are a class of widespread environmental carcinogens. Most of our knowledge of their mechanisms of metabolic activation to DNA-binding "ultimate carcinogenic" metabolites has come from analysis of the DNA interaction products formed by these highly reactive intermediates. Studies of their role in forming DNA-binding intermediates identical to those formed in vivo from the PAH itself have also allowed identification of the particular cytochrome P450 enzymes involved in activating various structural classes of carcinogenic PAHs. It has been established that PAHs, after metabolic activation in vivo, are capable of inducing mutations in oncogenes and, by inducing multiple mutations, may result in tumors. PAHs also cause changes in cellular gap-junction communication similar to those caused by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. Thus, PAHs may also act through a promotional mechanism in addition to serving as tumor initiators. Previous studies on these mechanisms are described and summarized.

Regulatory mechanisms to control tissue α-tocopherol

“…The CYP1A subfamily are key enzymes in the metabolic activation of numerous environmental xenobiotics, including many that enter the body via the respiratory system. Metabolic activation by the CYP1A subfamily of enzymes results in the production of highly reactive intermediates that have been shown to damage DNA [39,40]. Thus induction of this enzyme in either the liver or lung may lead to increased tissue damage.…”

The relationship between DNA adduct formation by benzo[a]pyrene and expression of its activation enzyme cytochrome P450 1A1 in rat

“…BaP and other PAHs are produced mainly by incomplete combustion of organic matter and are ubiquitous in the environment, leading to measurable background levels of exposure in the general population (IARC, 2010). Beside the inhalation of polluted air, the main sources of exposure are tobacco smoke and diet (Baird et al, 2005;Hamouchene et al, 2011;Phillips and Venitt, 2012). Chronic exposure of laboratory animals to BaP has been associated with the development of cancer, primarily in the skin, stomach and lungs (IARC, 2010).…”

“…BaP requires metabolic activation catalyzed by cytochrome P450 (CYP) enzymes prior to reaction with DNA (Baird et al, 2005). Of the CYP enzymes, CYP1A1 is one of the most important enzymes in the metabolic activation of BaP to species forming DNA adducts (Baird et al, 2005;Hamouchene et al, 2011), in combination with microsomal epoxide hydrolase (mEH).…”

“…Of the CYP enzymes, CYP1A1 is one of the most important enzymes in the metabolic activation of BaP to species forming DNA adducts (Baird et al, 2005;Hamouchene et al, 2011), in combination with microsomal epoxide hydrolase (mEH). First, CYP1A1 oxidizes BaP to an epoxide that is then converted to a dihydrodiol by mEH (i.e.…”

Synthesis of 13C2-benzo[a]pyrene and its 7,8-dihydrodiol and 7,8-dione implicated as carcinogenic metabolites

“…The most studied activation path involves cytochrome P-450 [CYP] mediated formation of a dihydrodiol (BP-7,8-diol) followed by its oxidation to a diol epoxide (BPDE). 3,11 A second pathway entails aldo-keto reductase-mediated oxidation of BP-7,8-diol to a catechol that enters into a redox cycle with O 2 to form a quinone (BP 7,8-dione) and reactive oxygen species (ROS) that attack DNA. 12,13 A third pathway has also been proposed that entails peroxidase-mediated oxidation of BP to a radical-cation that reacts with DNA to form depurinated adducts.…”