Lung Cancer: Mechanisms and Markers—Carcinogens Other Than Asbestos

Many carcinogenic chemicals, including polycyclic aromatic hydrocarbons, present in combustion products and tobacco smoke, enter cells as procarcinogens and require metabolic activation by cytochrome P450 (CYP) enzymes to exert their deleterious effects, including binding to DNA and formation of DNA adducts which, if not repaired, may lead to mutations in critical genes and cancer initiation. The induction of oxygen radical damage is considered the main mechanism of particle and metal carcinogenesis. In workplace air many carcinogens exist as complex mixtures, in which chemical compounds are bound to metal and mineral particles of respirable size. In lung cells, the components of complex mixtures induce oxidative stress as well as activation of chemical procarcinogens via intermingled pathways that may potentiate the DNA damage caused by either particle or chemical carcinogen alone. Carcinogenic metals are thought to induce oxidative stress-mediated DNA damage. Recent studies have shown that carcinogenic metals may replace metal ions, such as iron and zinc, in critical enzymes involved in DNA repair, histone methylation, and hypoxic signaling, for example. Epigenetic carcinogenic mechanisms have recently been found to play a larger role than previously thought, in environmental carcinogenesis.