Experimental Biology and Medicine 227:894-899 (2002)
© 2002 Society for Experimental Biology and Medicine
SYMPOSIA
Lycopene and the Lung
Lenore Arab*,1,
Susan Steck-Scott
and
Aaron T. Fleishauer*
1 Departments of Epidemiology and
Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599
 |
Abstract
|
|---|
The human lung, due to the oxidative and ozone stress to which it is exposed, is particularly vulnerable to oxidative damage. Concentrations of dietary antioxidants in the lung epithelial lining and lining fluids may provide protection against oxidative damage. A randomized clinical trial was conducted to study the effects of supplemental, carotenoid-rich vegetable juice (V-8) on lung function macrophage levels of carotenoids and in moderating ozone-induced lung damage. Healthy young adults (n = 23) were exposed to 0.4 ppm ozone in a chamber for 2 hr after either 2 weeks of antioxidant supplementation (including one can of V-8 juice daily) or placebo. Mean lung concentrations of lycopene increased by 12%, and lung epithelial cell DNA damage as measured by the Comet Assay decreased 20% in supplemented subjects. No change in peripheral blood lymphocyte DNA damage was observed as evidenced by no change in mean comet area or length in supplemented or placebo subjects. We were not able to separate the effects of lycopene from other carotenoids or antioxidants administered in this study; however, lycopene is the predominant carotenoid in V-8 (it represents 88% of total carotenoids). A review of the epidemiologic literature providing evidence for the effect of lycopene (diet or serum) or tomatoes on the risk of lung cancer reveals 27 observational epidemiologic studies (18 case-control and nine cohort studies) reporting relative risk (RR) estimates. RR estimates for cohort studies ranged from 0.63 to 1.24 (mean RR = 0.93, SD = 0.16). Odds ratios (OR) for case-control studies ranged from 0.27 to 0.93 (mean OR = 0.61, SD = 0.16). Both plasma levels (RR = 1.01, OR = 0.37) and estimated intakes of lycopene from dietary sources (mean RR = 0.93, RR range = 0.80–1.05; mean OR = 0.67, OR range = 0.27–0.93) were examined. Seventeen studies, three of which were cohorts, reported their results at the level of tomato consumption rather than, or in addition to, lycopene consumption (mean RR = 0.89, RR range = 0.63–1.24; mean OR = 0.61, OR range = 0.37–0.80). The published epidemiologic literature shows an interaction between study design and the relationship between lycopene and/ or tomatoes and risk of lung cancer. Overall, cohort studies did not show an association, whereas case-control studies showed a decreased risk with greater consumption of lycopene and tomatoes. Altough lycopene can be found in the human lung, and there is evidence, albeit weak, for a protective association with lung cancer, its biologic role remains to be elucidated.
Key Words: lycopene • antioxidants • lung function
|
Introduction
|
|---|
The lung is a large organ that is extremely susceptible to oxidative stresses. The volume of oxygen that passes through the lung is so great that it is likely to be extremely vulnerable unless there are multiple levels of antioxidant protection. The lung operates under a higher oxygen pressure environment than other internal organs. This can result in the conversion of high concentrations of antioxidants into pro-oxidants. In addition, the presence of other oxidants such as ozone can enhance risk of oxidative damage (1). Ozone is prone to react with and change the structures of organic compounds. Levels of ambient ozone in many areas of the U.S. exceed the National Ambient Air Quality Standards (2). Among other things, ozone has been shown to functionally affect the lung capacity (3, 4).
To protect against these vulnerabilities, a number of antioxidant defenses are present in the lung epithelial lining fluids, as well as within the lung cells. Ascorbic acid and tocopherols have been studied in this context (5). Tocopherols are believed to be, by sheer mass, the first line of defense against membrane oxidation. Ascorbic acid levels are known to be positively related to pulmonary function (6). Both lycopene and ß-carotene have been measured in lung tissue, from autopsy study and from bronchial lavage, lending credence to the possibility that carotenoids are a lung defense mechanism despite the fact that their concentrations are much lower than that of 
-tocopherol (7–10). The roles of the carotenoids are not well defined, although it can reasonably be hypothesized that if carotenoids serve as antioxidants, their effect in this environment should be evident. Human studies are needed to prove the bioavailability of lycopene and other carotenoids in the lung, the responsiveness of these substances to insult, and their potential for prevention of functional damage.
|
Lycopene and Other Lung Functions
|
|---|
Aside from the risk of lung cancer, which is a rare event and is strongly associated with smoke exposure, there is potential for carotenoids to protect lung integrity and lung function. Greater levels of lycopene and other carotenoids in the lung may provide an additional level of protection against oxidative and ozone induced damage. Several biochemical mechanisms might explain the protective effects of carotenoids in the human lung. Concentrations of carotenoids in addition to the other antioxidant vitamins in the lung epithelial lining and lining fluids can provide protection against oxidative damage.
The relationships between dietary antioxidants and clinical outcomes of lung dysfunction, such as wheezing, bronchitis, emphysema, asthma, and chronic, nonspecific lung disease have been examined in observational studies (reviewed in Refs. 11 and 12). These have confirmed the associations with vitamin C often (13–15) and vitamin E less often (15).
Other epidemiologic studies have examined the relationship between dietary antioxidants and markers of lung function (6, 16–18). In the NHANES 1 study, a random sample of the U.S. population in the 1970s, spirometric measures in 2500 adults were positively associated with vitamin C intakes, in particular with FEV1 as the outcome (6). In The Netherlands, both vitamin C and ß-carotene intakes were associated with higher FEV1 and forced vital capacity (FVC) in a large (n = 6555) adult population aged 20–59 (16). In the UK, reported intakes of both vitamins C and E were associated with greater FEV1 and FVC (17). In a study of men from three European countries, FEV was positively associated with vitamin E intake in Finland and with ß-carotene intake in The Netherlands (18). Another population of 1600 adults free from respiratory disease also demonstrated an association between lower vitamin E (or lutein/zeaxanthian) and lower forced vital capacity (19).
Although controlled clinical trials have confirmed the vitamin C and vitamin E effects on lung function (20–23), the examination of carotenoids, particularly those other than ß-carotene, has been largely overlooked. To study the uptake of lycopene in the lung and the effects of exercise and ozone exposure on plasma levels and lung levels, we conducted a randomized clinical trial of placebo versus vegetable juice in combination with a supplement of vitamins E and C. This involved bronchial lavage after exposure to air or ozone and exercise in a temperature- and moisture-controlled chamber.
|
Antioxidants and Lung: The Antioz Study
|
|---|
In collaboration with the Environmental Protection Agency (EPA) to test whether antioxidants can modify lung damage, we have studied the effects of supplementation of carotenoid-rich vegetable juice (V-8) on lung macrophage levels of carotenoids. We investigated whether dietary carotenoids are found in the lung, if they respond to oxidative stress, and if they impact lung function. In this randomized clinical trial, we found that the lung accumulated lycopene, and that the supplementation reduced DNA damage as measured by the Comet Assay.
The ANTIOZ Study: Ozone Exposure and Antioxidant Supplementation.
Ozone is a potent oxidant and has been shown to decrease lung function and increase inflammation in humans, which points to a causative role for ozone in lung diseases such as asthma and lung cancer. A randomized placebo-controlled clinical trial was conducted at the EPA to examine whether antioxidant supplementation could protect the human lung from the adverse effects of ozone exposure.
Twenty-three healthy, nonsmoking subjects (21 men and two women) between the ages of 18 and 35 years were enrolled in the study. Volunteers were excluded if their medical history revealed any of the following: cardiovascular disease, pulmonary disease and/or allergy including hay fever or dust allergies, asthma, chronic bronchitis, chronic exposure to dusts, irritants or allergens, hypertension, allergy to lidocaine or other local anesthetics, or any food allergies. Most subjects were not regular vitamin supplement users, but those that took supplements were instructed to stop supplement use at least 90 days prior to entry into the study.
Subjects were placed on a fruit- and vegetable-restricted diet for 1 week. All subjects were then exposed to ambient air while exercising intermittently for 2 hr in a Plexiglas and steel chamber as described previously (24). Blood samples were drawn and lung function was assessed before and after exposure. After the exposure, a bronchoscopy and bronchoalveolar lavage (BAL) was performed. Subjects were then randomized into either placebo (n = 12) or supplement groups (n = 11), and they maintained the low fruit and vegetable diet for 2 weeks. Supplemented subjects received one can of vegetable juice, 250 mg of vitamin C, and 50 IU of -tocopherol daily, and placebo subjects received one can of orange soda and a placebo pill consisting of a corn oil capsule daily. After 2 weeks of intervention, subjects were exposed to 0.4 ppm ozone in the chamber with intermittent exercise for 2 hr. Again, blood samples were drawn, lung function was assessed before and after the exposure, and another bronchoscopy and BAL were performed on all subjects post-exposure. The study timeline is presented in Figure 1
.
The main findings of the study regarding the effects on lung function and inflammation were recently published (24). The supplemented subjects experienced 30% and 24% smaller decrements in FEV1 and FVC, respectively, than the placebo subjects. Markers of inflammation in the lung, however, were not different between the supplemented and placebo subjects. This suggests that antioxidants may have a role in protecting the lung from the adverse effects of ozone exposure on lung function, but not in mediating the inflammatory response.
We also measured DNA damage using the Comet Assay in peripheral blood leukocytes before and after each exposure and in lung epithelial cells after each exposure. We found no significant change in DNA damage in the blood leukocytes in response to either ozone or antioxidant supplementation (25). However, we did observe a significant 20% increase in single-strand breaks in lung epithelial cells of placebo subjects from the baseline bronchoscopy after air exposure to the second bronchoscopy after ozone exposure, and no change in single-strand breaks in lung epithelial cells of supplemented subjects (26). This suggests that antioxidants may protect the lung from DNA damage associated with increased oxidative stress caused by ozone exposure.
We were not able to separate the effects of lycopene from those of other carotenoids or antioxidants administered in this study. However, lycopene was the predominant carotenoid in the vegetable juice supplement. The amount of lycopene in the vegetable juice supplement, as measured by high-performance liquid chromatography (HPLC), was 23 mg/day as compared with 2 mg/day ß-carotene, 0.7 mg/day -carotene, 0.4 mg/day lutein, and 0.1 mg/day zeaxanthin. We measured carotenoids using HPLC in the lung macrophages obtained from the BAL procedure and found that lycopene was also the predominant carotenoid following supplementation, representing 55% of total carotenoids found in these cells (Steck S, Arab L, Craft N, Samet J, unpublished data). After the supplementation period, lung macrophage concentrations of lycopene increased on average 0.56 ng/100,000 cells, representing a 12% increase from baseline (27). It is not clear how well lung macrophage carotenoid concentrations reflect lung epithelial cell concentrations. Only one study has examined this question and observed a correlation of r = 0.33 (P = 0.19) between BAL cell and lung tissue total carotenoid concentration in 12 smokers (10).
Lycopene and Lung Cancer: Observation Epidemiology.
Many case-control and cohort studies have examined lycopene-rich diets and lung cancer (28–54). Tables I and II identify 27 observational studies (18 case-control and nine cohort) that have reported RR estimates for the intake of tomato products, lycopene from dietary sources, or lycopene in serum and risk of lung cancer. The majority of RR estimates for the highest categories of intake or serum concentrations suggest a protective effect. In fact, every case-control OR for the highest category of consumption compared with the lowest is below the null value. The ORs reported in case-control studies ranged from 0.27 to 0.93. Whereas three of nine cohort studies reported RR estimates greater than 1.0, none of these were statistically significant. The RR estimates for cohort studies ranged from 0.63 to 1.24. Therefore, no consistent relationship among cohort studies is evident.
View this table:
[in this window]
[in a new window]
|
Table I. Epidemiological Case-Control Studies of Lycopene Intake from Diet or Plasma and Tomato Consumption and Risk of Lung Cancer
|
|
View this table:
[in this window]
[in a new window]
|
Table II. Epidemiological Cohort Studies of Lycopene Intake from Diet or Plasma and Tomato Consumption and Risk of Lung Cancer
|
|
The range of intake across studies showed considerable heterogeneity. As noted in Tables I and II
, high intakes for tomato consumption ranged from greater than 0.8 servings per month to greater than or equal to daily consumption. The range for the highest categories of lycopene from diet was greater than 0.01 mg per day to more than 18.2 mg per day. Closer inspection of the highest categories across all case-control studies revealed that daily consumption of tomatoes was associated with the lowest ORs (28–32) as compared with the highest categories in other studies that set the cut-point for tomato consumption to include lower frequency and quantities of use. This trend was not observed in cohort studies (33) where daily consumption of tomatoes was not associated with risk, except for results from the Nurses Health Study (34) where a modest reduced risk (RR = 0.80) with at least daily consumption was reported. No dose-response relationship between increasing tomato consumption and decreasing risk of lung cancer was observed.
Examining the influence of study design, cohort studies assess exposures prior to the onset of disease, whereas case-control studies evaluate exposures subsequent to disease. Case-control studies can misclassify individuals as a result of recall bias, whereas cohort studies with a single measurement do not account for changes in diet over time. In the case-control studies represented in this review, most dietary assessment tools focused on the year or years (28–29) prior to diagnosis or interview. Recall bias is likely when disease influences an individual’s recent diet, and that person is more likely to recall recent diet.
Other sources of bias may include the measurement tool, and in most studies, a single food frequency questionnaire is the method to assess exposure status. The food frequency questionnaire in these studies ranged from 27 to 130 items. Misclassification could be introduced if all sources of lycopene are not represented or, if coded, sources were not adjusted for bioavailability differences between raw and cooked foods. For lycopene, the major sources are tomatoes and tomato products (tomato juice and tomato sauces). Nonetheless, it is uncertain why RR estimates from case-control studies and cohort studies were consistently divergent.
|
Discussion
|
|---|
The plausibility of a relationship between lycopene and oxidative protection in the lung rests upon the known chemistry of lycopene, in vitro studies on its antioxidant potential, and the documented presence of lycopene in lung epithelium and lung macrophages. The epidemiologic literature suggests that diets rich in tomato products are associated with lower lung cancer rates. However, this can also be said for ß-carotene, yet interventions failed to show a protective effect. The epidemiology also suggests an interaction between study design and the relationship between lycopene and/ or tomatoes and risk of lung cancer. Cohort studies do not show an association, whereas case-control studies consistently show a protective effect for the highest categories of consumption. This may be due to the decreased attention to quantitative dietary assessment in cohort studies, measurement error in case-control studies, or the differences in bioavailability assessment between studies. Also, cohort studies in general have fewer cases in the exposed subgroups than do case-control studies. All told, the strength of association in epidemiologic studies between lycopene intake and lung cancer risk is inconsistent.
Regarding the hypothesis that supplementation with food-based carotenoids can influence the lung environment, we have been able to demonstrate the uptake of lycopene into the lung after supplementation and ozone exposure. This finding opens the door to research on ways by which we can prevent environmental damage to the lung through dietary selection.
|
Footnotes
|
|---|
1 To whom requests fro reprints should be addressed at Department of Epidemiology, University of North Carolina, Suite 2105E, Mcgavran Greenberg Building, CB# 7435, Chapel Hill, NC 27599-7435. E-mail: lenore{at}unc.edu 
|
References
|
|---|
- Pryor WA. Mechanisms of radical formation from reactions of ozone with target molecules in the lung. Free Radic Biol Med 17:451–465, 1994.[Medline]
- Lippman M. Ozone. In: Rom WN, Ed. Environmental and Occupational Medicine (3rd ed). Philadelphia: Lippincott-Raven Publishers, pp601–615, 1998.
- McDonnell WF, Horstman DH, Abddul-Salaam S, House DE. Reproducibility of individual response to ozone exposure. Am Rev Respir Dis 131:36–40, 1985.[Medline]
- McDonnell WF, Koren R, Devlin SA, Abdul-Salaam S, Ives P, O’Neil J. Biochemical and cellular correlates of changes in pulmonary function and symptoms in humans exposed to ozone. Am Rev Respir Dis 141:A72–A76, 1990.
- Cross CE, van der Vliet A, O’Neill CA, Louie S, Halliwell B. Oxidants, antioxidants, and respiratory tract lining fluids. Environ Health Perspect 102(Suppl 10):185–191, 1994.
- Schwartz J, Weiss ST. Relationship between dietary vitamin C intake and pulmonary function in the First National Health and Nutrition Examination Survey (NHANES I). Am J Clin Nutr 59:110–114, 1994.[Abstract/Free Full Text]
- Schmitz HH, Poor CL, Wellman RB, Erdman JW. Concentrations of selected carotenoids and vitamin A in human liver, kidney and lung tissue. J Nutr 121:1613–1621, 1991.
- Redlich CA, Blaner WS, Van Bennekum AM, Chung JS, Clever SL, Holm CT, Cullen MR. Effect of supplementation with ß-carotene and vitamin A on lung nutrient levels. Cancer Epidemiol Biomarkers Prev 7:211–214, 1998.[Abstract]
- Hilbert J, Mohensin V. Adaptation of lung antioxidants to cigarette smoking in humans. Chest 110:916–920, 1996.[Abstract/Free Full Text]
- Redlich CA, Grauer JN, Van Bennekum AM, Clever SL, Ponn RB, Blaner WS. Characterization of carotenoid, vitamin A, and -tocopherol levels in human lung tissue and pulmonary macrophages. Am J Respir Crit Care Med 154:1436–1443, 1996.[Abstract]
- Hatch GE. Asthma, inhaled oxidants, and dietary antioxidants. Am J Clin Nutr 61:625S–630S, 1995.[Abstract/Free Full Text]
- Hatch GE. Vitamin C and asthma. In: Packer L, Fuchs J, Eds. Vitamin C in Health and Disease. New York: Marcel Dekker, pp279–294, 1997.
- Schwartz J, Weiss ST. Dietary factors and their relation to respiratory symptoms. The Second National Health and Nutrition Examination Survey. Am J Epidemiol 132:67–76, 1990.[Abstract/Free Full Text]
- Soutar A, Seaton A, Brown K. Bronchial reactivity and dietary antioxidants. Thorax 52:166–170, 1997.[Abstract]
- Troisi RJ, Willett WC, Weiss ST, Trichopoulos D, Rosner B, Speizer FE. Prospective study of diet and adult-onset asthma. Am J Respir Crit Care Med 151:1401–1408, 1995.[Abstract]
- Grievink L, Smit HA, Ocke MC, van’t Veer P, Kromhout D. Dietary intake of antioxidant (pro)-vitamins, respiratory symptoms and pulmonary function: the MORGEN study. Thorax 53:166–171, 1998.[Abstract/Free Full Text]
- Britton JR, Pavord ID, Richards KA, et al. Dietary antioxidant vitamin intake and lung function in the general population. Am J Respir Crit Care Med 151:1383–1387, 1995.[Abstract]
- Tabak C, Smit HA, Rasanen L, et al. Dietary factors and pulmonary function: a cross-sectional study in middle-aged men from three European countries. Thorax 54(11):1021–1026, 1999.[Abstract/Free Full Text]
- Schünemann HJ, McCann S, Grant BJB, Trevisan M, Muti P, Freudenheim JL. Lung function in relation to intake of carotenoids and other antioxidant vitamins in a population-based study. Am J Epidemiol 155:463–471, 2002.[Abstract/Free Full Text]
- Chatharn MD, Eppler JH Jr, Sauder LR, Green D, Kulle TJ. Evaluation of the effects of vitamin C on ozone-induced bronchoconstriction in normal subjects. Ann N Y Acad Sci 498:269–279, 1987.[Medline]
- Trenga C, Koenig J, Williams P. Dietary antioxidants and ozone-induced bronchial hyper-responsiveness in adults with asthma. Arch Environ Health 56:242–249, 2001.[Medline]
- Grievink L, Jansen SM, van’t Veer P, Brunekreef B. Acute effects of ozone on pulmonary function of cyclists receiving antioxidant supplements. Occup Environ Med 55(1):13–17, 1998.[Abstract/Free Full Text]
- Romieu I, Meneses F, Ruiz S, Sienra JJ, Huerta J, White MC, Etzel RA. Effects of air pollution on the respiratory health of asthmatic children living in Mexico City. Am J Respir Crit Care Med 154(2 Pt 1):300–307, 1996.[Abstract]
- Samet JM, Hatch GE, Horstman D, Steck-Scott S, Arab L, Bromberg PA, Levine M, McDonnell W, Devlin RB. Effect of antioxidant supplementation on ozone-induced lung injury in human subjects. Am J Respir Crit Care Med 164:819–825, 2001.[Abstract/Free Full Text]
- Steck SE, Madden M, Samet J, Kohlmeier L. Effect of ozone exposure and antioxidant supplementation on DNA damage in human blood leukocytes. Fed Am Soc Exp Biol J 13:14, 1999.
- Steck SE, Madden M, Samet J, Arab L. The prevention of ozone-induced DNA damage in human lung epithelial cells by dietary antioxidants. Fed Am Soc Exp Biol J 14:4, 2000.
- Steck SE, Samet J, Craft N, Kohlmeier L. Correlation between lung macrophage and plasma carotenoid levels in humans. Fed Am Soc Exp Biol J 13(4):14, 1999.
- Bond GG, Thompson FE, Cook RR. Dietary vitamin A and lung cancer: results of a case-control study among chemical workers. Nutr Cancer 9(2-3):109–121, 1987.[Medline]
- Brennan P, Fortes C, Butler J, et al. A multi-center case control study of diet and lung cancer among non-smokers. Cancer Causes Control 11:49–58, 2000.[Medline]
- Axelsson G, Liljeqvist T, Andersson L, et al. Dietary factors and lung cancer among men in west Sweden. Int J Epidemiol 25:32–39, 1996.[Abstract/Free Full Text]
- Harris RW, Key TJ, Silcocks PB, et al. A case-control study of dietary carotene in men with lung cancer and in men with other epithelial cancers. Nutr Cancer 15:63–68, 1991.[Medline]
- Goodman MT, Kolonel LN, Wilkens LR, et al. Dietary factors in lung cancer prognosis. Eur J Cancer 28(2-3):495–501, 1992.
- Fraser GE, Beeson WL, Phillips RL. Diet and lung cancer in California Seventh-day Adventists. Am J Epidemiol 133:683–693, 1991.[Abstract/Free Full Text]
- Speizer FE, Colditz GA, Hunter DJ, et al. Prospective study of smoking, antioxidant intake, and lung cancer in middle-aged women (USA). Cancer Causes Control 10:475–482, 1999.[Medline]
- Agudo A, Esteve MG, Pallares C, et al. Vegetable and fruit intake and the risk of lung cancer in women in Barcelona. Spain Eur J Cancer 33:1256–1261, 1997.
- Candelora EC, Stockwell HG, Armstrong AW, et al. Dietary intake and risk of lung cancer in women who never smoked. Nutr Cancer 17:263–270, 1992.[Medline]
- De Stefani E, Boffetta P, Deneo-Pellegrini H, et al. Dietary carotenoids and lung cancer risk: a case-control study in Uruguay. Nutr Cancer 34:100–110, 1999.[Medline]
- Forman MR, Yao SX, Graubard BI, et al. The effect of dietary intake of fruits and vegetables on the odds ratio of lung cancer among Yunnan tin miners. Int J Epidemiol 21:437–441, 1992.[Abstract/Free Full Text]
- Garcia-Closas R, Agudo A, Gonzalez CA, et al. Intake of specific carotenoids and flavonoids and the risk of lung cancer in women in Barcelona, Spain. Nutr Cancer 32:154–158, 1998.[Medline]
- Le Marchand L, Yoshizawa CN, Kolonel LN, et al. Vegetable consumption and lung cancer risk: a population-based case-control study in Hawaii. J Natl Cancer Inst 81:1158–1164, 1989.[Abstract/Free Full Text]
- Le Marchand L, Hankin JH, Kolonel LN, et al. Intake of specific carotenoids and lung cancer risk. Cancer Epidemiol Biomarkers Prev 2:183–187, 1993.[Abstract]
- Li Y, Elie M, Blaner WS, et al. Lycopene, smoking and lung cancer. Proc Am Assoc Cancer Res 38:A758, 1997.
- Mayne ST, Janerich DT, Greenwald P, et al. Dietary ß-carotene and lung cancer risk in U.S. nonsmokers. J Natl Cancer Inst 86:33–38, 1994.[Abstract/Free Full Text]
- Muscat JE, Huncharek M. Dietary intake and the risk of malignant mesothelioma. Br J Cancer 73:1122–1125, 1996.[Medline]
- Sankaranarayanan R, Varghese C, Duffy SW, et al. A case-control study of diet and lung cancer in Kerala, south India. Int J Cancer 58:644–649, 1994.[Medline]
- Swanson CA, Mao BL, Li JY, et al. Dietary determinants of lung cancer risk: results from a case-control study in Yunnan Province. China Int J Cancer 50:876–880, 1992.
- Ziegler RG, Colavito EA, Hartge P, et al. Importance of -carotene, ß-carotene, and other phytochemicals in the etiology of lung cancer. J Natl Cancer Inst 88:612–615, 1996.[Free Full Text]
- Comstock GW, Helzlsouer KJ, Bush TL. Prediagnostic serum levels of carotenoids and vitamin E as related to subsequent cancer in Washington County, Maryland. Am J Clin Nutr 53(1 Suppl):260S–264S, 1991.[Abstract/Free Full Text]
- Knekt P, Jarvinen R, Seppanen R, et al. Dietary antioxidants and the risk of lung cancer [see comments]. Am J Epidemiol 134:471–479, 1991.[Abstract/Free Full Text]
- Knekt P, Jarvinen R, Teppo L, et al. Role of various carotenoids in lung cancer prevention. J Natl Cancer Inst 91:182–184, 1999.[Free Full Text]
- Kvale G, Bjelke E, Gart JJ. Dietary habits and lung cancer risk. Int J Cancer 31:397–405, 1983.[Medline]
- Michaud DS, Feskanich D, Rimm EB, et al. Intake of specific carotenoids and risk of lung cancer in two prospective US cohort studies. Am J Clin Nutr 72:990–997, 2000.[Abstract/Free Full Text]
- Steinmetz KA, Potter JD, Folsom AR. Vegetables, fruit, and lung cancer in the Iowa Women’s Health Study. Cancer Res 53:536–543, 1993.[Abstract/Free Full Text]
- Voorrips LE, Goldbohm RA, Brants HAM, et al. A prospective cohort study on antioxidant and folate intake and male lung cancer risk. Cancer Epidemiol Biomarkers Prev q9: 357–365, 2000.
This article has been cited by other articles:
|
|
|
|
 
J. A. Satia, A. Littman, C. G. Slatore, J. A. Galanko, and E. White
Long-term Use of {beta}-Carotene, Retinol, Lycopene, and Lutein Supplements and Lung Cancer Risk: Results From the VITamins And Lifestyle (VITAL) Study
Am. J. Epidemiol.,
April 1, 2009;
169(7):
815 - 828.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. E. Rhodes
Dietary effects on carotenoid composition in the marine harpacticoid copepod Nitokra lacustris
J. Plankton Res.,
March 1, 2007;
29(suppl_1):
i73 - i83.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X.-D. Wang
Can Smoke-Exposed Ferrets Be Utilized to Unravel the Mechanisms of Action of Lycopene?
J. Nutr.,
August 1, 2005;
135(8):
2053S - 2056S.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. D. Davis
Use of Exfoliated Cells from Target Tissues to Predict Responses to Bioactive Food Components
J. Nutr.,
June 1, 2003;
133(6):
1769 - 1772.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
