Carcinogenic Polycyclic Aromatic Hydrocarbons

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are formed upon incomplete combustion of organic matter. Due to the abundant use of fossil energy sources, PAHs are readily detectable as ubiquitous contaminants in the environment. The great interest in this group of chemicals originated on the observation in animal tumor models that some member compounds possessed strong carcinogenic activity in skin, lung, breast, and other organs. Epidemiological meta-analyses confirmed that heavy exposures to mixtures of PAHs entail a substantial risk to develop cancer in certain organs. No matter what kind of source, humans are always exposed to mixtures of PAH with different degrees of biological activity. From all hydrocarbons detectable in the human environment the most intensively studied example benzo[a]pyrene (B[a]P) has been traditionally used as an indicator for carcinogenic PAHs. About four decades ago it was proposed that there is a significant positive correlation between the binding to DNA and the biological potency of carcinogenic PAHs. In more recent years it became clear that vicinal diol-epoxides of PAHs that contain the epoxy moiety in a sterically crowded bay or fjord region are the actual DNA-binding metabolites that mediate the biological effects associated with their parent structures. Hence, PAHs would not be carcinogenic if they were not stereoselectively metabolized by cytochrome P450-dependent monooxygenases (CYPs). The DNA adduct level at a given time point is an integrated product of PAH’s toxicokinetic and toxicodynamic behavior, including metabolic activation and detoxification prior to covalent binding, as well as the effectiveness of the repair of those DNA lesions that have been formed. Covalent PAH-DNA adducts are fixed as mutations if left to error-prone excision repair, misrepair, or replication errors during early S phase. If such somatic mutations occur in proto-oncogenes (e.g., K-Ras) and/or tumor suppressor genes (e.g., TP53), they can contribute to the aggravation of neoplastic growth through the processes of tumor promotion and progression. Given the chemical complexity of most environmental matrices, it seems difficult, if not impossible, to uncover causative relationships between certain forms of human cancer and the exposure to particular carcinogenic PAHs though. Nevertheless, molecular epidemiology has been able to point to the role of individual compounds and to extract their contribution from the overall biological response on environmental mixtures. One of the most well worked-out examples is the crucial role of B[a]P in the etiology of human lung cancer based on its presence in cigarette smoke. Its important role in tumor initiation is supported by several lines of evidence such as (1) increased levels of PAH activating CYP enzymes in lung cancer patients compared to controls, (2) a correlation between pulmonary levels of activating CYP enzymes and bulky B[a]P–DNA adduct levels in human lung tissue from cancer patients, (3) increased levels of B[a]P–DNA adducts in lung tissue of smokers compared to nonsmokers, and (4) the coincidence of mutational hotspots at certain codons of K-Ras or TP53 and B[a]P–DNA adduct hotspots as the preceding lesions found at the same sites.