help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on April 5, 2007, doi:10.1164/rccm.200611-1655PP
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200611-1655PPv1
176/2/113    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Related articles in AJRCCM
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ben-Zaken Cohen, S.
Right arrow Articles by Sin, D. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ben-Zaken Cohen, S.
Right arrow Articles by Sin, D. D.
American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 113-120, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200611-1655PP

Pulmonary Perspective

The Growing Burden of Chronic Obstructive Pulmonary Disease and Lung Cancer in Women

Examining Sex Differences in Cigarette Smoke Metabolism

Sigal Ben-Zaken Cohen1, Peter D. Paré1, S. F. Paul Man1 and Don D. Sin1

1 The James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul's Hospital, and the Division of Respirology, Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Don D. Sin, M.D., James Hogg iCAPTURE Center, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada. E-mail: dsin{at}mrl.ubc.ca

ABSTRACT

Smoking-related lung diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer are growing epidemics in women in the United States and elsewhere. Although some of this disturbing trend in women can be attributed to changing smoking habits, there is emerging evidence that women may be biologically more susceptible to the harmful effects of cigarette smoke than are men. Estrogen and related compounds may up-regulate the expression of cytochrome P450 (CYP) enzymes in lungs and liver, which are involved in the metabolism of various constituents of cigarette smoke. Although metabolism of foreign substances is usually beneficial in eliminating potential toxins from the body, in some instances the metabolic process can transform harmless substances into toxic chemicals through a process called metabolic bioactivation. One important xenobiotic substrate for CYP enzymes in cigarette smoke is polycyclic aromatic hydrocarbon, which in its native form is relatively harmless in small doses but upon bioactivation by CYP enzymes, can become very toxic substances for the lungs. In this article, we explore CYP and other related pathways as potential mechanisms and targets of future research and novel discoveries to curb the growing epidemic of COPD and lung cancer in women.

Key Words: gender • sex • cytochrome P450 • chronic obstructive pulmonary disease • lung cancer

EPIDEMIOLOGY OF SMOKING-RELATED DISORDERS

Chronic Obstructive Pulmonary Disease: The Silent Epidemic In Women
The two principal tobacco-related respiratory illnesses, chronic obstructive pulmonary disease (COPD) and lung cancer, are major health problems in the United States and elsewhere. In the United States, over the past 30 years, the mortality rate for COPD has increased by 103%, whereas other major causes of mortality, such as heart disease, cancer, stroke, and accidents, have decreased by 52, 3, 63, and 41%, respectively (1). In women, between 1980 and 2000, the annual mortality rate for COPD increased by 291% and hospitalization increased by 43%. In men, the mortality rate increased by a more modest 60%, whereas the hospitalization rate increased by only 12% (2). By 2020, COPD mortality and hospitalization rates are expected to double globally, making COPD the third leading cause of mortality and the fifth leading cause of disability worldwide (3). In the Western world, this massive increase in COPD-related morbidity and mortality will be driven largely by the increasing burden of disease in women (4).

The epidemiology of lung cancer is no less disturbing. Every year, approximately 1.35 million people die of lung cancer worldwide. In women, lung cancer is the leading cause of cancer deaths with a mortality rate that is approximately 60% higher than that for breast cancer (5). The annual female age-standardized lung cancer mortality increased by 4.2% between 1982 and 1990 and by 1.7% between 1990 and 1995. In men, the annual mortality rate increased by a very modest 0.4% between 1982 and 1991 and decreased by 1.9% between 1991 and 2001 (5).

The reasons for the increase in COPD and lung cancer in women remain a mystery. One possibility is survival bias. Because fewer women die of cardiovascular diseases, more women may die of other major causes of mortality, such as cancer and COPD. Another possibility relates to differential use of tobacco between men and women. Although over the past decade female smoking rates in the United States have increased relative to male rates, there continues to be fewer female than male adult smokers (18 vs. 23%) (6). Moreover, even when women smoke, they, on average, consume fewer cigarettes per day and have lower salivary cotinine levels compared with men. Thus, smoking patterns alone cannot fully account for the rising rates of COPD and lung cancer in women.

Increased Susceptibility of Female Smokers to COPD
Data from large epidemiologic studies support the notion that women have increased risk for COPD. Cigarette smoke exposure during childhood and adolescence impairs lung growth more severely in girls than in boys. Gold and colleagues found that, among adolescents, smoking five or more cigarettes a day, as compared with never-smokers, was associated with a 1.09%/year reduction in the growth rate of FEV1 in girls, whereas for boys, smoking reduced FEV1 growth by only 0.20%/year (7). In adulthood, female smokers demonstrate accelerated decline in FEV1 and FVC compared with male smokers (8). The disparity in FEV1 decline is most striking in heavy smokers, suggesting a synergistic interaction between sex and tobacco exposure on the rate of FEV1 decline over time (9). Moreover, for any given pack-years of smoking, female smokers are two to three times more likely to be hospitalized and die of COPD compared with male smokers (9). On the positive side, female smokers who stop smoking experience larger improvements in FEV1 (as % of predicted) compared with male sustained quitters (10).

Women and Lung Cancer
Whether women have increased risk for lung cancer is controversial. Although several case-control studies reported increased risk for women (11–13), data from large prospective studies have been mixed. Bain and colleagues showed that, in current smokers and lifetime nonsmokers, there was no difference in the risk for lung cancer between men and women, although in former smokers, women had a slightly higher risk of lung cancer (relative risk, 1.29; p < 0.05) (14). However, in a large population-based lung cancer screening program of smokers (n = 7,498 women and 9,427 men), women were almost twice as likely to be diagnosed with lung cancer on screening computed tomography compared with men (odds ratio, 1.9) (15). Notwithstanding the ongoing controversy regarding sex-related differences in the risk for lung cancer, there are major phenotypic and histologic differences in lung cancer between men and women. For example, peripheral lung adenocarcinomas are more common in women than in men; this is in contrast to squamous cell carcinomas, which are more common in men. COPD is also an important risk factor for lung cancer. In both men and women, the risk of lung cancer increases with decreasing lung function. However, the risk is amplified in women. For the same marginal decrease in FEV1, adjusted for smoking history, women are approximately two times more likely to develop lung cancer than are men (see Figure 1) (16).


Figure 1
View larger version (12K):
[in this window]
[in a new window]

  		Figure 1. The risk of lung cancer in men and women as a function of FEV1. p < 0.001 for the comparison of slopes between men and women. The FEV1 data are divided in quintiles. The quintile data are derived from multiple studies and each study used slightly different FEV1 cutoffs to form the quintile groups. Because of this, the quintile groups from the combined dataset are presented as a range of FEV1 rather than as one discrete FEV1 value. Quintile 1 is approximately <60 to 77% of predicted; Quintile 2 is 61 to 89% of predicted; Quintile 3 is 76 to 100% of predicted; Quintile 4 is 86 to 112% of predicted; Quintile 5 is > 100 to 113% of predicted. Adapted by permission from Reference 16.

 
Because the major risk factor for both COPD and lung cancer is cigarette smoking, in this article we will review sex-related differences in metabolism of the constituents of cigarette smoke and how that might impact on the susceptibility of men and women to these disorders. A hypothetical biological model of why female smokers might be at increased risk of COPD and lung cancer is shown in Figure 2.


Figure 2
View larger version (22K):
[in this window]
[in a new window]

  		Figure 2. Hypothetical model of why female smokers might be more susceptible to chronic obstructive pulmonary disease (COPD) and lung cancer. Cigarette smoke up-regulates a number of cytochrome P450 (CYP) enzymes in the lungs, which in turn metabolize nicotine and other components of cigarette smoke into various intermediate chemicals. Some of these products cause lung damage by forming reactive oxygen species (ROS). *The ROS may bind to DNA within local cells, leading to the formation of DNA adducts, which impair cellular replication and repair. Women may be particularly vulnerable to the adverse effects of cigarette smoke because (1) estrogen can up-regulate the expression and activity of CYP enzymes; (2) women have smaller airways and increased bronchial responsiveness, which may cause an increase in particle deposition deep within the lung; (3) women have decreased DNA repair capacity; and (4) a higher frequency of p53 mutations.See text for details.

 
CIGARETTE SMOKE METABOLISM

See Table E1 in the online supplement for details.

Constituents of Cigarette Smoke
Tobacco smoke consists of "sidestream" and "mainstream" smoke. Sidestream smoke is produced by the burning tip of cigarettes, whereas mainstream smoke is produced by the mouth end of cigarettes (17). Cigarette smoke exists in two forms: a gaseous and a particulate phase. The gaseous phase is formed predominantly by carbon monoxide, ammonia, dimethylnitrosamine, formaldehyde, hydrogen cyanide, and acrolein (17). The main components of the particulate phase are nicotine, tar, benzene, and benzo[a]pyrene. Tobacco also contains nitrosamine, NNK (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone), minor alkaloids (e.g., nornicotine, anatabine, and anabasine), N-nitroso derivatives and polycyclic aromatic hydrocarbons (PAHs). With smoking, these chemicals are rapidly absorbed and metabolized in the body via oxidation (first phase) and conjugation (second phase). The oxidative phase occurs in a two-step process mediated by cytochrome P450 (CYP) (step 1) and aldehyde oxidase (step 2) (18).

CYP and Bioactivation
There are at least 57 different CYP genes and 24 pseudogenes, which can be further subdivided into 17 different families (19). The main CYP responsible for the first phase reaction is CYP2A6, which belongs to the CYP2 subfamily. The human CYP2 family is a heterogeneous group of enzymes. It contains the subfamilies CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, CYP2F, and CYP2J (20). CYP2B6, CYP2D6, CYP2E1, CYP2F1, and CYP2J2 are the only functional members in their respective subfamilies. CYP2A6 is involved in the conversion of nicotine to NNK and nicotine to nornicotine through the N-demethylation pathway (21). Genetic polymorphisms of CYP2A6 (especially a deletion) have been associated with alterations in smoking behavior and with decreased risk of lung cancer (22). The majority of CYPs are expressed in human liver, but they are also expressed on a smaller scale in extrahepatic tissues such as the skin and the lungs. A summary of human CYPs is provided in Table 1. Although metabolism of foreign substances is usually beneficial in eliminating potential toxins from the body, in some instances CYP-mediated metabolic process can transform harmless substances into toxic chemicals through a process called metabolic bioactivation. For instance, in its native form, benzo[a]pyrene (BP), a PAH, is relatively harmless. However, when BP is oxidized to BP-7,8-diol by CYP1A1, and to a lesser extent by the CYP3A4 enzyme, it becomes a potent procarcinogen (see Figure 3) (23). Another example is naphthalene (NP), which is the most abundant PAH in sidestream smoke. CYP1A2, CYP2E1, and CYP3A4 enzymes metabolize NP to NP-1,2-epoxide, which, in turn, is bioactivated to 1,4-naphthoquinole and 1,2-naphthoquinone (24), both of which are known carcinogens and toxins to the lungs (see Figure 3). Interestingly, in mouse models, it has been shown that cells in distal airways are three to five times more sensitive to the toxic effects of NP compared with cells in the trachea or the proximal bronchi (25). These findings may have interesting implications, as it is generally accepted that the distal airways are predominantly affected in COPD, and adenocarcinoma of the lung often begins in the small airways. Female smokers have increased expression of CYP enzymes in lungs compared with male smokers, which is related to increased estradiol-beta expression (26). Estrogen receptor-{alpha} may also up-regulate CYP1B1 expression at the transcriptional level and CYP1A1 expression at the translational level (27). Interestingly, CYPs are also involved in the bioactivation of 17beta-estradiol, which may produce a positive feedback loop (28).


Figure 3
View larger version (20K):
[in this window]
[in a new window]

  		Figure 3. A potential mechanism of lung toxicity related to bioactivation and metabolism of two types of polycyclic aromatic hydrocarbons: benzo[a]pyrene (BP) and naphthalene (NP). Metabolism of BP and NP by cytochrome P450 (CYP) generates intermediate chemicals, which are more toxic than the parent compounds. Some of these intermediate products can damage to the lungs directly by generating reactive oxygen species (ROS) or indirectly through the creation of DNA adducts.

 

View this table:
[in this window]
[in a new window]

  		TABLE 1. VARIOUS CYTOCHROME P450 ENZYMES AND THEIR EXPRESSION IN THE LUNGS AND LIVER OF HUMAN SUBJECTS

 
WHY WOULD FEMALE SMOKERS BE AT INCREASED RISK FOR LUNG CANCER AND COPD?

Sex Differences in Cigarette Metabolism
With few notable exceptions, there is a marked scarcity of published studies that have evaluated the potential sex-related differences in cigarette metabolism and their possible impact on lung diseases. The few studies that have examined this topic have focused mostly on nicotine and have been small in size and limited in scope, leading to inconsistent and at times conflicting results. In the largest study to date, Benowitz and colleagues studied 270 healthy volunteers who were twins and 16 who were siblings of twins and exposed them to deuterium-labeled nicotine and cotinine intravenously (29). They found that women compared with men had faster plasma clearance of both nicotine and cotinine, greater conversion of nicotine to cotinine, and significantly higher trans-3' hydroxycotinine-d2 (3HC-d2)–to–cotinine-d2 ratio (0.27:0.19; p < 0.001) and 3HC-d4–to–cotinine-d4 ratio (0.32:0.21; p < 0.001). Because 3HCs are metabolites of cotinine generated predominantly by the CYP2A6 pathway (30), these data suggest that women compared with men have accelerated metabolism of nicotine and cotinine related to CYP activity. Interestingly, these investigators also found that women on an estrogen-only birth control pill had a significantly higher ratio of 3HC-d2 to cotinine-d2 (0.39: 0.25; p < 0.05) and a higher ratio of 3HC-d4 to cotinine-d4 (0.46:0.28; p < 0.05) compared with women not on any hormonal supplements. Progesterone had the opposite effect (29). These data suggest that estrogen or its related metabolites may be responsible for accelerating nicotine and cotinine metabolism in women, possibly through the CYP pathways.

Genetic Studies
The alleles for all CYP isoenzymes are located on autosomal chromosomes. Thus, sex-related allelic variations would not be expected (31). However, other factors, such as sex hormones, may modulate the expression and activity of CYP enzymes, which in turn can lead to sex-related differences in xenobiotic metabolism (32). The CYP3A enzyme is one such example. CYP3A enzymes, especially CYP3A4 and CYP3A5, are involved in drug metabolism and account for 30% of the CYP enzymes in the liver. CYP3A activity is significantly higher in women than in men (32). CYP2A6, the main enzyme responsible for nicotine metabolism, may also be differentially expressed between men and women. One recent study showed that females, without any genetic alterations in the CYP2A6 gene, had significantly higher CYP2A6 levels in the liver compared with men (33). CYP1A1 is an enzyme that bioactivates PAH, leading to the production of reactive oxidative species. In one study, female smokers demonstrated higher mRNA expression of CYP1A1 enzymes in the lungs compared with male smokers; the CYP1A1 expression in turn was positively associated with DNA adduct levels in the lungs of patients with lung cancer (34). Another enzyme that bioactivates PAH is GSTM1, which participates in the phase 2 response. Polymorphisms of both CYP1A1 and GSTM1 genes are associated with a higher risk for lung cancer in women (35). However, expression data should be interpreted cautiously because alterations in the expression pattern may not necessarily translate into changes in function. Nevertheless, these studies suggest that women compared with men have increased activity of certain CYP enzymes, including CYP2A6 and CYP1A1. The potential relevance of this observation has been explored in animal experiments.

Animal Studies
Van Winkle and colleagues found that when he injected NP (200 mg/kg) into Swiss Webster mice, the female mice demonstrated greater airway injury than did male mice (36). Female lungs contained greater amounts of NP metabolites and, in particular, NP dihydrodiol, which is a known toxin to bronchial epithelial cells and to Clara cells (37). Western blots from microdissected mouse distal airways showed higher expression of CYP enzymes in female compared with male mice. Forkert and coworkers showed that, when mice were exposed to 1,1-dichloroethylene, a chemical that is selectively metabolized by CYP enzymes, female mice had significantly greater CYP activity and higher levels of 1,1-dichloroethylene metabolites compared with male mice (38). These metabolites in turn incited a vigorous inflammatory reaction and oxidative stress in the airways, which over time led to scarring and narrowing of the airways (39). Taken together, these animal studies indicate that, when females are exposed to cigarette smoke (and its components), they mount a more vigorous inflammatory reaction and generate more oxidative stress in the airways than males, possibly due to increased levels of toxic metabolites related to differential activity of CYP enzymes. Because chronic inflammation and oxidative stress may be instrumental in amplifying (and perhaps even inducing) mutagenic damage and promoting tumor growth and metastasis, sex-related differences in lung inflammation may also explain the increased risk of lung cancer in female smokers.

Other Mechanisms
There may be other mechanisms that could contribute to increased risk of smoking-related lung disorders in female smokers.

Lung inflammation and oxidative stress as a potential links between COPD and lung cancer.
Bronchial hyperresponsiveness (BHR) has been associated with increased risk of COPD progression and COPD mortality (40). Approximately 87% of female smokers with mild to moderate COPD demonstrate increased bronchial responsiveness, whereas only 63% of male smokers demonstrate BHR (41). Importantly, in men, the major risk factors for BHR are asthma and atopy, whereas in females, the single most important risk factor is cigarette smoking, especially for those who have severe BHR (42). In men, smoking status has little or no effect on BHR (42). Although there are many factors that govern BHR, airway inflammation plays a significant role in the process. There is now a general consensus that inflammation and oxidative stress are important components in the pathobiology of COPD, which may contribute to COPD progression, systemic inflammation, and oxidative stress and associated morbidity and mortality (43). BHR may also increase deposition of small aerosolized particles by 19% (44).

p53 mutations and DNA adducts.
Of the various genetic alterations in lung cancer, abnormalities in the tumor suppressor gene p53 are among the most frequent and important events occurring in approximately 50% of non–small cell lung cancers and in more than 70% in small cell lung cancers (45). There may be major sex differences in the expression of the p53 gene that may predispose women to lung cancer. Kure and colleagues found in 55 patients with lung cancer that female patients had a higher frequency of G:C->T:A mutations in the p53 gene and a larger burden of hydrophobic DNA adducts in the nontumorous lung tissue compared with male patients, even though female patients had smoked fewer cigarettes before surgery (46). Cheng and coworkers found that in lifetime nonsmokers who developed lung cancer, female patients had significantly higher DNA adduct levels in the nontumorous sections of lung compared with male patients (47). In never-smokers who developed lung cancer, the occurrence of G:C->T:A transversion was approximately three times higher in female than in male patients (48).

One of the important first steps in lung carcinogenesis is the formation of DNA adducts. DNA adducts alter DNA structure, which in turn modifies its ability to replicate, translate, and repair. If left unrepaired, DNA adducts can cause genetic mutations, and if the affected gene is an oncogene or a tumor suppressor gene, carcinogenesis can ensue (49). Not surprisingly, smokers have higher levels of adducts in their nontumorous lung tissue compared with nonsmokers. Female smokers have higher adduct levels compared with male smokers, and this difference becomes even larger when the adduct levels are adjusted for cigarette smoking and expressed as adducts/pack-year or adducts/cigarettes consumed per day (34).

In addition, women have DNA repair capacity that is 10 to 15% lower than that in men (p < 0.001) (50). Because of increased burden of DNA adducts and DNA mutations, women who have reduced DNA repair capacity have significantly increased risk of developing lung cancer than do men with reduced DNA repair capacity. For example, when a women has a DNA repair capacity that is lower than 7.0%, her risk of lung cancer increases by approximately sevenfold, whereas in men, the risk is increased by only twofold (50). These data suggest that women have a major imbalance in the injury and repair processes at the molecular level that may predispose them to lung cancer.

The role of sex hormones.
Estrogen has the ability to induce differentiation and maturation of the lung. Increased estrogen levels are known risk factors for lung cancer in women. Estrogen may contribute to lung tumor genesis in a number of different ways. There are two known estrogen receptors in lung tissues: estrogen receptor-{alpha} and receptor-beta. Estrogen receptor-{alpha} is a ligand-activated transcription factor. Its overexpression has been associated with the development of estrogen-dependent cancers, such as breast and endometrial carcinoma (51). In lungs, activation of this receptor induces lung differentiation and maturation. Estrogen receptor-beta is the predominant estrogen receptor in the lungs. Upon stimulation by estradiol, this receptor causes proliferation of lung cancer cells, which can be abrogated by estrogen receptor antagonists. Estrogen also induces CYP enzyme–related pathways (27). Female smokers have increased lung expression of CYP enzymes compared with male smokers (in one study, female lungs had 2.4 times more mRNA than did male lungs; p = 0.016) (34). The increased CYP expression is related to estrogen levels (34). Stimulation of estrogen receptor in the lungs increases protein expression of CYP1A1 by 2.0-fold (34).

Consistent with these mechanisms, epidemiologic studies have shown an association between exogenous estrogens and development of lung adenocarcinoma in women. Using a case-control design, Taioli and Wynder (52), showed that women who used estrogen therapy had a higher risk of lung cancer. The risk for lung cancer was amplified in women who used estrogen and also smoked cigarettes. Ganti and colleagues showed that female smokers with lung cancer who received hormone replacement therapy (HRT) had a 47% reduction in mean survival compared with female smokers not receiving HRT. In contrast, in female nonsmokers, HRT was associated with only a 6% reduction in survival (53). These studies suggest a synergistic effect of estrogen and cigarette smoke on the development and progression of lung cancer.

Other environmental irritants.
Although cigarette smoke is the single most important risk factor for COPD and lung cancer, environmental pollution and chronic infections may play salient roles in 20 to 40% of the cases (54). For example, for every 10-µg/m3 rise in air pollution containing particles measuring less than 2.5 µm in diameter, the risk of COPD and lung cancer deaths increases by 6 to 8% (55). The risk appears in higher in women than in men (56), although future large studies are needed to validate these initial observations.

SUMMARY AND FUTURE DIRECTIONS

There is an epidemic of COPD and lung cancer in women across the Western world. The rates of COPD are now greater in women than in men, and within the next 20 years, there will be more women than men with lung cancer. Yet, disturbingly, very little is known regarding the mechanisms behind this epidemic. Women, for largely unknown reasons, appear particularly vulnerable to the adverse effects of cigarette smoking. Animal studies have raised the possibility that there may be important sex-related differences in the metabolism of some constituents of cigarette smoke (mediated largely by CYP enzymes), leading to increased production of carcinogenic and airway-toxic molecules in females. In addition, women appear more susceptible to DNA damage and more likely to develop DNA adducts when exposed to cigarette smoke, and at the same time, have decreased capacity for DNA repair. Although the causes for these observations are unclear, sex hormones play some role because it is known that estrogen can up-regulate CYP expression. CYPs in turn metabolize PAHs into highly reactive substances that bind to DNA, resulting in hydrophobic/aromatic DNA adducts. Clearly, additional animal and clinical studies are needed to determine the validity of this and other potential pathways to explain the epidemic of COPD and lung cancer in the female population and to develop novel strategies to curb the growing burden of these disorders in women.

FOOTNOTES

Supported by ICEBERGS (Interdisciplinary Capacity Enhancement: Bridging Excellence in Respiratory disease and Gender Studies), which is funded by The Canadian Institutes of Health Research. D.D.S. is supported by a Canada Research Chair Award and a Senior Scholarship from the Michael Smith Foundation for Health Research. He is also the holder of the St. Paul's Hospital Foundation/GlaxoSmithKline Professorship in COPD.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200611-1655PP on April 5, 2007

Conflict of Interest Statement: S.B.-Z.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.D.P. is the principal investigator of a project funded by GlaxoSmithKline (GSK) to develop CT-based algorithms to quantify emphysema and airway disease in COPD; with collaborators he has received approximately $300,000 to develop and validate these techniques. The funds he has applied solely to the research to support programs and technicians. He is also principal investigator of a Merck Frost–supported research program to investigate gene expression in the lungs of patients who have COPD. He and collaborators have received approximately $200,000 for this project. These funds have supported the technical personnel and expendables involved in the project. S.F.P.M. served on the GSK advisory board on September 2006. D.D.S. has received honoraria for speaking engagements from AstraZeneca in 2003 ($4,000), in 2004 ($3,000), and in 2005 ($11,000), and from GSK in 2003 ($4,000), in 2004 ($8,000), in 2005 ($6,500), and in 2006 ($10,000). D.D.S has also received unrestricted research funding as either the principal investigator or co-principal investigator from GSK in 2003 for $80,000 and in 2004 for $1.5 million; has also received $3,500 from GSK for consultancy work in 2004 and $1,500 in 2006.

Received in original form November 18, 2006; accepted in final form April 4, 2007

REFERENCES

  1. Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States, 1970–2002. JAMA 2005;294:1255–1259.[Abstract/Free Full Text]
  2. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive pulmonary disease surveillance: United States, 1971–2000. MMWR Surveill Summ 2002;51:1–16.[Medline]
  3. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020. Global Burden of Disease Study. Lancet 1997;349:1498–1504.[CrossRef][Medline]
  4. Rutten van-Molken MP, Feenstra TL. The burden of asthma and chronic obstructive pulmonary disease: data from the Netherlands. Pharmacoeconomics 2001;19:1–6.
  5. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10–30.[Abstract/Free Full Text]
  6. Centers for Disease Control and Prevention (CDC). State-specific prevalence of cigarette smoking and quitting among adults: United States, 2004. MMWR Morb Mortal Wkly Rep 2005;54:1124–1127.[Medline]
  7. Gold DR, Wang X, Wypij D, Speizer FE, Ware JH, Dockery DW. Effects of cigarette smoking on lung function in adolescent boys and girls. N Engl J Med 1996;335:931–937.[Abstract/Free Full Text]
  8. Xu X, Weiss ST, Rijcken B, Schouten JP. Smoking, changes in smoking habits, and rate of decline in FEV1: new insight into gender differences. Eur Respir J 1994;7:1056–1061.[Abstract]
  9. Prescott E, Bjerg AM, Andersen PK, Lange P, Vestbo J. Gender difference in smoking effects on lung function and risk of hospitalization for COPD: results from a Danish longitudinal population study. Eur Respir J 1997;10:822–827.[Abstract]
  10. Connett JE, Murray RP, Buist AS, Wise RA, Bailey WC, Lindgren PG, Owens GR. Changes in smoking status affect women more than men: results of the Lung Health Study. Am J Epidemiol 2003;157:973–979.[Abstract/Free Full Text]
  11. Risch HA, Howe GR, Jain M, Burch JD, Holowaty EJ, Miller AB. Are female smokers at higher risk for lung cancer than male smokers? A case-control analysis by histologic type. Am J Epidemiol 1993;138:281–293.[Abstract/Free Full Text]
  12. Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996;88:183–192.[Abstract/Free Full Text]
  13. Osann KE, Anton-Culver H, Kurosaki T, Taylor T. Sex differences in lung-cancer risk associated with cigarette smoking. Int J Cancer 1993;54:44–48.[Medline]
  14. Bain C, Feskanich D, Speizer FE, Thun M, Hertzmark E, Rosner BA, Colditz GA. Lung cancer rates in men and women with comparable histories of smoking. J Natl Cancer Inst 2004;96:826–834.[Abstract/Free Full Text]
  15. Henschke CI, Yip R, Miettinen OS. Women's susceptibility to tobacco carcinogens and survival after diagnosis of lung cancer. JAMA 2006;296:180–184.[Abstract/Free Full Text]
  16. Wasswa-Kintu S, Gan WQ, Man SF, Pare PD, Sin DD. Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: a systematic review and meta-analysis. Thorax 2005;60:570–575.[Abstract/Free Full Text]
  17. U.S. Surgeon General. The health consequences of smoking: chronic obstructive lung disease. Washington: U.S. Government Press Office; 1984.
  18. Cashman JR, Park SB, Yang ZC, Wrighton SA, Jacob P III, Benowitz NL. Metabolism of nicotine by human liver microsomes: stereoselective formation of trans-nicotine N'-oxide. Chem Res Toxicol 1992;5:639–646.[CrossRef][Medline]
  19. Guengerich FP. Cytochrome P450: what have we learned and what are the future issues? Drug Metab Rev 2004;36:159–197.[CrossRef][Medline]
  20. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211–2221.[Free Full Text]
  21. Yamanaka H, Nakajima M, Fukami T, Sakai H, Nakamura A, Katoh M, Takamiya M, Aoki Y, Yokoi T. CYP2A6 AND CYP2B6 are involved in nornicotine formation from nicotine in humans: interindividual differences in these contributions. Drug Metab Dispos 2005;33:1811–1818.[Abstract/Free Full Text]
  22. Miyamoto M, Umetsu Y, Dosaka-Akita H, Sawamura Y, Yokota J, Kunitoh H, Nemoto N, Sato K, Ariyoshi N, Kamataki T. CYP2A6 gene deletion reduces susceptibility to lung cancer. Biochem Biophys Res Commun 1999;261:658–660.[CrossRef][Medline]
  23. Dix TA, Marnett LJ. Metabolism of polycyclic aromatic hydrocarbon derivatives to ultimate carcinogens during lipid peroxidation. Science 1983;221:77–79.[Abstract/Free Full Text]
  24. Wilson AS, Davis CD, Williams DP, Buckpitt AR, Pirmohamed M, Park BK. Characterisation of the toxic metabolite(s) of naphthalene. Toxicology 1996;114:233–242.[CrossRef][Medline]
  25. Plopper CG, Macklin J, Nishio SJ, Hyde DM, Buckpitt AR. Relationship of cytochrome P-450 activity to Clara cell cytotoxicity: III. Morphometric comparison of changes in the epithelial populations of terminal bronchioles and lobar bronchi in mice, hamsters, and rats after parenteral administration of naphthalene. Lab Invest 1992;67:553–565.[Medline]
  26. Spivack SD, Hurteau GJ, Fasco MJ, Kaminsky LS. Phase I and II carcinogen metabolism gene expression in human lung tissue and tumors. Clin Cancer Res 2003;9:6002–6011.[Abstract/Free Full Text]
  27. Han W, Pentecost BT, Pietropaolo RL, Fasco MJ, Spivack SD. Estrogen receptor alpha increases basal and cigarette smoke extract-induced expression of CYP1A1 and CYP1B1, but not GSTP1, in normal human bronchial epithelial cells. Mol Carcinog 2005;44:202–211.[CrossRef][Medline]
  28. Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR. 17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proc Natl Acad Sci USA 1996;93:9776–9781.[Abstract/Free Full Text]
  29. Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P III. Female sex and oral contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther 2006;79:480–488.[CrossRef][Medline]
  30. Dempsey D, Tutka P, Jacob P III, Allen F, Schoedel K, Tyndale RF, Benowitz NL. Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin Pharmacol Ther 2004;76:64–72.[CrossRef][Medline]
  31. Smith G, Stubbins MJ, Harries LW, Wolf CR. Molecular genetics of the human cytochrome P450 monooxygenase superfamily. Xenobiotica 1998;28:1129–1165.[CrossRef][Medline]
  32. Meibohm B, Beierle I, Derendorf H. How important are gender differences in pharmacokinetics? Clin Pharmacokinet 2002;41:329–342.[CrossRef][Medline]
  33. Al Koudsi N, Mwenifumbo JC, Sellers EM, Benowitz NL, Swan GE, Tyndale RF. Characterization of the novel CYP2A6*21 allele using in vivo nicotine kinetics. Eur J Clin Pharmacol 2006;62:481–484.[CrossRef][Medline]
  34. Mollerup S, Ryberg D, Hewer A, Phillips DH, Haugen A. Sex differences in lung CYP1A1 expression and DNA adduct levels among lung cancer patients. Cancer Res 1999;59:3317–3320.[Abstract/Free Full Text]
  35. Patel JD, Bach PB, Kris MG. Lung cancer in US women: a contemporary epidemic. JAMA 2004;291:1763–1768.[Abstract/Free Full Text]
  36. Van Winkle LS, Gunderson AD, Shimizu JA, Baker GL, Brown CD. Gender differences in naphthalene metabolism and naphthalene-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 2002;282:L1122–L1134.[Abstract/Free Full Text]
  37. Chichester CH, Buckpitt AR, Chang A, Plopper CG. Metabolism and cytotoxicity of naphthalene and its metabolites in isolated murine Clara cells. Mol Pharmacol 1994;45:664–672.[Abstract]
  38. Forkert PG, Dowsley TF, Lee RP, Hong JY, Ulreich JB. Differential formation of 1,1-dichloroethylene-metabolites in the lungs of adult and weanling male and female mice: correlation with severities of bronchiolar cytotoxicity. J Pharmacol Exp Ther 1996;279:1484–1490.[Abstract/Free Full Text]
  39. Seymour BW, Friebertshauser KE, Peake JL, Pinkerton KE, Coffman RL, Gershwin LJ. Gender differences in the allergic response of mice neonatally exposed to environmental tobacco smoke. Dev Immunol 2002;9:47–54.[CrossRef][Medline]
  40. Hospers JJ, Postma DS, Rijcken B, Weiss ST, Schouten JP. Histamine airway hyper-responsiveness and mortality from chronic obstructive pulmonary disease: a cohort study. Lancet 2000;356:1313–1317.[CrossRef][Medline]
  41. Kanner RE, Connett JE, Altose MD, Buist AS, Lee WW, Tashkin DP, Wise RA. Gender difference in airway hyperresponsiveness in smokers with mild COPD. The Lung Health Study. Am J Respir Crit Care Med 1994;150:956–961.[Abstract]
  42. Paoletti P, Carrozzi L, Viegi G, Modena P, Ballerin L, Di Pede F, Grado L, Baldacci S, Pedreschi M, Vellutini M, et al. Distribution of bronchial responsiveness in a general population: effect of sex, age, smoking, and level of pulmonary function. Am J Respir Crit Care Med 1995;151:1770–1777.[Abstract]
  43. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 2003;22:672–688.[Abstract/Free Full Text]
  44. Kohlhaufl M, Brand P, Scheuch G, Meyer TS, Schulz H, Haussinger K, Heyder J. Increased fine particle deposition in women with asymptomatic nonspecific airway hyperresponsiveness. Am J Respir Crit Care Med 1999;159:902–906.[Abstract/Free Full Text]
  45. Takahashi T, Nau MM, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, Levitt M, Pass H, Gazdar AF, Minna JD. p53: a frequent target for genetic abnormalities in lung cancer. Science 1989;246:491–494.[Abstract/Free Full Text]
  46. Kure EH, Ryberg D, Hewer A, Phillips DH, Skaug V, Baera R, Haugen A. p53 mutations in lung tumours: relationship to gender and lung DNA adduct levels. Carcinogenesis 1996;17:2201–2205.[Abstract/Free Full Text]
  47. Cheng YW, Hsieh LL, Lin PP, Chen CP, Chen CY, Lin TS, Su JM, Lee H. Gender difference in DNA adduct levels among nonsmoking lung cancer patients. Environ Mol Mutagen 2001;37:304–310.[CrossRef][Medline]
  48. Toyooka S, Tsuda T, Gazdar AF. The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat 2003;21:229–239.[CrossRef][Medline]
  49. Poirier MC, Santella RM, Weston A. Carcinogen macromolecular adducts and their measurement. Carcinogenesis 2000;21:353–359.[Abstract/Free Full Text]
  50. Wei Q, Cheng L, Amos CI, Wang LE, Guo Z, Hong WK, Spitz MR. Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study. J Natl Cancer Inst 2000;92:1764–1772.[Abstract/Free Full Text]
  51. Pearce ST, Jordan VC. The biological role of estrogen receptors alpha and beta in cancer. Crit Rev Oncol Hematol 2004;50:3–22.[Medline]
  52. Taioli E, Wynder EL. Re: endocrine factors and adenocarcinoma of the lung in women. J Natl Cancer Inst 1994;86:869–870.[Free Full Text]
  53. Ganti AK, Sahmoun AE, Panwalkar AW, Tendulkar KK, Potti A. Hormone replacement therapy is associated with decreased survival in women with lung cancer. J Clin Oncol 2006;24:59–63.[Abstract/Free Full Text]
  54. Mannino DM, Watt G, Hole D, Gillis C, Hart C, McConnachie A, Davey Smith G, Upton M, Hawthorne V, Sin DD, et al. The natural history of chronic obstructive pulmonary disease. Eur Respir J 2006;27:627–643.[Free Full Text]
  55. Pope CA III, Burnett RT, Thun MJ, Calle EE, Krewski D, Ito K, Thurston GD. Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. JAMA 2002;287:1132–1141.[Abstract/Free Full Text]
  56. Lam WK. Lung cancer in Asian women: the environment and genes. Respirology 2005;10:408–417.[CrossRef][Medline]

Related articles in AJRCCM:

COPD and Lung Cancer Have Come a Long Way ...Baby
David M. Mannino
AJRCCM 2007 176: 108-109. [Full Text]  



This article has been cited by other articles:


Home page
 Eur Respir JHome page
P. J. Barnes and B. R. Celli
Systemic manifestations and comorbidities of COPD
Eur. Respir. J., May 1, 2009; 33(5): 1165 - 1185.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
A. Punturieri, E. Szabo, T. L. Croxton, S. D. Shapiro, and S. M. Dubinett
Lung Cancer and Chronic Obstructive Pulmonary Disease: Needs and Opportunities for Integrated Research
J Natl Cancer Inst, April 15, 2009; 101(8): 554 - 559.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
J. P. de Torres, C. G. Cote, M. V. Lopez, C. Casanova, O. Diaz, J. M. Marin, V. Pinto-Plata, M. M. de Oca, H. Nekach, L. J. Dordelly, et al.
Sex differences in mortality in patients with COPD
Eur. Respir. J., March 1, 2009; 33(3): 528 - 535.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
Z. Hammoud, B. Tan, S. Badve, and R. M Bigsby
Estrogen promotes tumor progression in a genetically defined mouse model of lung adenocarcinoma
Endocr. Relat. Cancer, June 1, 2008; 15(2): 475 - 483.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
S. Dubey and C. A. Powell
Update in Lung Cancer 2007
Am. J. Respir. Crit. Care Med., May 1, 2008; 177(9): 941 - 946.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
W. MacNee
Update in Chronic Obstructive Pulmonary Disease 2007
Am. J. Respir. Crit. Care Med., April 15, 2008; 177(8): 820 - 829.
[Full Text] [PDF]

Home page
 Eur Respir JHome page
L. M. Fabbri, F. Luppi, B. Beghe, and K. F. Rabe
Complex chronic comorbidities of COPD
Eur. Respir. J., January 1, 2008; 31(1): 204 - 212.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
D. D. Sin, L. Greaves, and S. Kennedy
The Tip of the "ICEBERGS": A National Conference to Combat the Growing Global Epidemic of COPD in Women
Proceedings of the ATS, December 1, 2007; 4(8): 669 - 670.
[Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
P. G. Camp and S. M. Goring
Gender and the Diagnosis, Management, and Surveillance of Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, December 1, 2007; 4(8): 686 - 691.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
B. Lamprecht, L. Schirnhofer, F. Tiefenbacher, B. Kaiser, S. A. Buist, M. Studnicka, and P. Enright
Six-Second Spirometry for Detection of Airway Obstruction: A Population-based Study in Austria
Am. J. Respir. Crit. Care Med., September 1, 2007; 176(5): 460 - 464.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. M. Mannino
COPD and Lung Cancer Have Come a Long Way ...Baby
Am. J. Respir. Crit. Care Med., July 15, 2007; 176(2): 108 - 109.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200611-1655PPv1
176/2/113    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Related articles in AJRCCM
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ben-Zaken Cohen, S.
Right arrow Articles by Sin, D. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ben-Zaken Cohen, S.
Right arrow Articles by Sin, D. D.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2007 American Thoracic Society