Research Letters

Genetic variation of CYP2A6, smoking, and risk of cancer

The toxicity of environmental chemicals, that is, nontherapeutic agents, to respiratory tissues is described in significant detail throughout this volume. In the vast majority of cases, these environmental toxicants are inhaled chemicals that interact with respiratory cells on a contact basis, after inhalation. There is, however, an ever-expanding repertoire of chemicals that produce selective or specific toxicity to cells within the respiratory system after systemic circulation throughout the biological system. Many of these chemicals are therapeutic agents such as bleomycin (BLM) or amiodarone (AM), and some are nontherapeutic chemicals such as 3-methylindole (3MI), aflatoxin B₁ (AFB₁), butylated hydroxytoluene (BHT), halogenated hydrocarbons, naphthalenes, paraquat (1,19-dimethyl-4,49-bipyridilium, PQ), the pyrrolizidine alkaloids (PZAs), and the substituted furans that are ingested and circulated systemically. This article deals with chemicals that are known to cause damage to respiratory tissues following exposure and the mechanisms of their toxicity, which is generally mediated by oxidative metabolism of the chemicals to reactive electrophiles by cytochrome P450 enzymes in cells of the respiratory tract. These compounds are generally toxic to nonciliated bronchiolar epithelial cells and alveolar epithelial cells of the gas exchange region although some agents are highly toxic to nasal epithelial or pulmonary endothelial cells. The purpose of this chapter is to provide chemical and biochemical insights into the generalized mechanisms of toxicity of certain circulating pneumotoxicants, through the enumeration and compilation of a few examples of well-documented, chemically induced lung damage.

Cigarette smoking is the major cause of lung cancer in the United States and worldwide. Tobacco products are estimated to cause approximately 90% of lung cancer cases. Experimental studies in laboratory animals have collectively demonstrated the carcinogenicity of cigarette smoke and cigarette smoke condensates. There are over 5000 identified chemicals and more than 60 known carcinogens in cigarette smoke, with polycyclic aromatic hydrocarbons and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone likely being the most important respiratory carcinogens. The carcinogenicity of cigarette smoke can also be enhanced by the presence of tumor promoters and cocarcinogens. The reaction of carcinogens with DNA can cause mutations and, if unrepaired, can lead to the activation of oncogenes or the inactivation of tumor suppressors. Epigenetic changes may also occur from exposure to tobacco carcinogens, leading to a change in gene expression. While the majority of lung cancer results from cigarette smoking, only 15% of smokers get lung cancer. Studies indicate that this may be due to genetic factors that contribute to a person’s susceptibility to tobacco-induced cancers. Biomarkers have been developed to monitor uptake and activation of tobacco carcinogens, and perhaps could be used to predict susceptibility to lung cancer. Chemoprevention has developed as an approach to prevent or delay the onset of tobacco-induced lung cancer. However, cessation of tobacco products is the best way to prevent lung cancer.

Studies of the effects of smoking on leukocyte telomere length (LTL) using cigarettes smoked per day or pack years smoked (PYS) present limitations. Reported high levels of smoking may not increase toxin exposure levels proportionally. Nicotine metabolism ratio (NMR) predicts total cigarette puff volume and overall exposure based on total N-nitrosamines, is highly reproducible and independent of time since the last cigarette. We hypothesized that smokers with higher NMRs will exhibit increased total puff volume, reflecting efforts to extract more nicotine from their cigarettes and increasing toxin exposure. In addition, higher levels of smoking could cause a gross damage in LTL. The urinary cotinine, 3-OH cotinine and nicotine levels of 147 smokers were analyzed using a LC/MS system Triple-Q6410. LTL and CYP2A6 genotype was determined by PCR in blood samples. We found a significant association between NMR and CYP2A6 genotype. Reduction in LTL was seen in relation to accumulated tobacco consumption and years smoking when we adjusted for age and gender. However, there were no significant differences between NMR values and LTL. In our study the higher exposure was associated with lower number of PYS. Smokers with reduced cigarette consumption may exhibit compensatory smoking behavior that results in no reduced tobacco toxin exposure. Our results suggest that lifetime accumulated smoking exposure could cause a gross damage in LTL rather than NMR or PYS. Nevertheless, a combination of smoking topography (NMR) and consumption (PYS) measures may provide useful information about smoking effects on health outcomes.

Arachidonic acids are converted to eicosanoid mediators by different enzyme systems: cyclooxygenase, lipoxygenase, and cytochrome P450 (CYP) monooxygenase pathways (ω/ω-1-hydroxylases and epoxygenases). Of 57 putatively functional human CYPs, only about a dozen enzymes are responsible for xenobiotic metabolism. CYP2 family is the predominant epoxygenase isoform abundantly expressed in the endothelium, myocardium, and kidney in humans. Numerous studies have demonstrated the cardiovascular protective effects of CYP epoxygenases and eicosatrienoic acids ranging from vasodilation, antihypertensive, proangiogenesis, antiatherosclerosis, and cardiac protection. The roles of CYP2 family and their metabolites in inflammation and cancer biology have recently attracted great attention. Here, we review the recent progress on polymorphisms, distribution and function of CYP2 family, and their roles in inflammation and cancer.

The toxicity of environmental chemicals, that is, nontherapeutic agents, to respiratory tissues is described in significant detail throughout this volume. In the vast majority of cases, these environmental toxicants are inhaled chemicals that interact with respiratory cells on a contact basis, after inhalation. There is, however, an ever-expanding repertoire of chemicals that produce selective or specific toxicity to cells within the respiratory system after systemic circulation throughout the biological system. Many of these chemicals are therapeutic agents such as bleomycin (BLM) or amiodarone (AM) and some are nontherapeutic chemicals such as 3-methylindole (3MI), aflatoxin B1 (AFB1), butylated hydroxytoluene (BHT), halogenated hydrocarbons, naphthalenes, paraquat (1,19-dimethyl-4, 49-bipyridilium, PQ), the pyrrolizidine alkaloids (PZAs), and the substituted furans that are ingested and circulated systemically. This chapter deals with chemicals that are known to cause damage to respiratory tissues following exposure and the mechanisms of their toxicity, which is generally mediated by oxidative metabolism of the chemicals to reactive electrophiles by cytochrome P450 enzymes in cells of the respiratory tract. These compounds are generally toxic to nonciliated bronchiolar epithelial cells and alveolar epithelial cells of the gas exchange region, although some agents are highly toxic to nasal epithelial or pulmonary endothelial cells. The purpose of this chapter is to provide chemical and biochemical insights into the generalized mechanisms of toxicity of certain circulating pneumotoxicants, through the enumeration and compilation of a few examples of well-documented, chemically induced lung damage.