Polycyclic aromatic hydrocarbons: from metabolism to lung cancer.
Excessive exposure to polycyclic aromatic hydrocarbons (PAHs) often results in lung cancer, a disease with the highest cancer mortality in the United States. After entry into the lung, PAHs induce phase I metabolic enzymes such as cytochrome P450 (CYP) monooxygenases, i.e. CYP1A1/2 and 1B1, and phase II enzymes such as glutathione S-transferases, UDP glucuronyl transferases, NADPH quinone oxidoreductases (NQOs), aldo-keto reductases (AKRs), and epoxide hydrolases (EHs), via the aryl hydrocarbon receptor (AhR)-dependent and independent pathways. Humans can also be exposed to PAHs through diet, via consumption of charcoal broiled foods. Metabolism of PAHs through the CYP1A1/1B1/EH pathway, CYP peroxidase pathway, and AKR pathway leads to the formation of the active carcinogens diol-epoxides, radical cations, and o-quinones. These reactive metabolites produce DNA adducts, resulting in DNA mutations, alteration of gene expression profiles, and tumorigenesis. Mutations in xenobiotic metabolic enzymes, as well as polymorphisms of tumor suppressor genes (e.g. p53) and/or genes involved in gene expression (e.g. X-ray repair cross-complementing proteins), are associated with lung cancer susceptibility in human populations from different ethnicities, gender, and age groups. Although various metabolic activation/inactivation pathways, AhR signaling, and genetic susceptibilities contribute to lung cancer, the precise points at which PAHs induce tumor initiation remain unknown. The goal of this review is to provide a current state-of-the-science of the mechanisms of human lung carcinogenesis mediated by PAHs, the experimental approaches used to study this complex class of compounds, and future directions for research of these compounds.
*Department of Pediatrics, Baylor College of Medicine, Houston, Texas and Division of Extramural Research and Training, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Bhagavatula
B
Moorthy
*Department of Pediatrics, Baylor College of Medicine, Houston, Texas and Division of Extramural Research and Training, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Chun
C
Chu
*Department of Pediatrics, Baylor College of Medicine, Houston, Texas and Division of Extramural Research and Training, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Danielle J
DJ
Carlin
D065767:Activation, Metabolic; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced*; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*
D002273:Carcinogens; D011084:Polycyclic Aromatic Hydrocarbons; D003577:Cytochrome P-450 Enzyme System
Ah receptor; PAH; carcinogenesis; genetic susceptibility; lung cancer; metabolism; mixtures; polycyclic aromatic hydrocarbons