Carcinogenesis, Vol. 21, No. 12, 2245-2253,
December 2000
© 2000 Oxford University Press
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION |
Effects of physiological versus pharmacological ß-carotene supplementation on cell proliferation and histopathological changes in the lungs of cigarette smoke-exposed ferrets
1 Jean Mayer United States Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University and
2 Department of Biochemistry Tufts University School of Medicine, Boston, MA 02111, USA
There remains a remarkable discordance between the results of observational epidemiological studies and intervention trials using ß-carotene as a potential chemopreventive agent. One question that needs to be examined is whether the adverse outcomes of human ß-carotene trials are related to the large doses of ß-carotene that were administered. In the present study, ferrets were given a physiological (low) dose or a pharmacological (high) dose of ß-carotene supplementation (0.43 mg versus 2.4 mg/kg body wt/day, which is equivalent to 6 mg versus 30 mg/day in humans) and exposed to cigarette smoke for 6 months. We investigated the effects of these doses of ß-carotene on retinoid concentrations, expression of retinoic acid receptors (RARs), activator protein 1 (AP-1; c-Jun and c-Fos), cyclin D1, proliferating cellular nuclear antigen (PCNA), and histopathological changes in the lungs of both normal and cigarette smoke-exposed ferrets. Thirty-six male ferrets were treated in six groups—control, smoke-exposed (SM), low-dose ß-carotene (LBC), high-dose ß-carotene (HBC), low-dose ß-carotene plus smoke exposure (LBC+SM) or high-dose ß-carotene plus smoke exposure (HBC+SM)—for 6 months. Retinoic acid concentration and RARß gene expression, but not expression of RAR
and RAR
, was reduced in the lung tissue of HBC+SM, HBC, SM and LBC+SM ferrets, but not in that of LBC ferrets, as compared with the control group. Expression of AP-1 and PCNA was greater in HBC+SM, HBC, SM and LBC+SM ferrets, but not in the LBC ferrets, as compared with the control group. Increased amounts of cyclin D1 and keratinized squamous metaplasia were observed in the lung tissue of HBC+SM, HBC and SM groups but not in that of the LBC+SM, LBC or control groups. These data suggest that, in contrast with a pharmacological dose of ß-carotene, a physiological dose of ß-carotene in smoke-exposed ferrets has no potentially detrimental effects and may afford weak protection against lung damage induced by cigarette smoke.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F. Lian, D. E. Smith, H. Ernst, R. M. Russell, and X.-D. Wang Apo-10'-lycopenoic acid inhibits lung cancer cell growth in vitro, and suppresses lung tumorigenesis in the A/J mouse model in vivo Carcinogenesis, July 1, 2007; 28(7): 1567 - 1574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Puntoni, S. Zanardi, D. Branchi, S. Bruno, A. Curotto, M. Varaldo, P. Bruzzi, and A. Decensi Prognostic Effect of DNA Aneuploidy from Bladder Washings in Superficial Bladder Cancer Cancer Epidemiol. Biomarkers Prev., May 1, 2007; 16(5): 979 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Palozza, S. Serini, S. Trombino, L. Lauriola, F.O. Ranelletti, and G. Calviello Dual role of {beta}-carotene in combination with cigarette smoke aqueous extract on the formation of mutagenic lipid peroxidation products in lung membranes: dependence on pO2 Carcinogenesis, December 1, 2006; 27(12): 2383 - 2391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Russell The Multifunctional Carotenoids: Insights into Their Behavior J. Nutr., October 1, 2006; 136(10): 2690S - 2692S. [Full Text] [PDF]
|
|
|
|
 |
|
 N. N. Maserejian, E. Giovannucci, B. Rosner, A. Zavras, and K. Joshipura Prospective Study of Fruits and Vegetables and Risk of Oral Premalignant Lesions in Men Am. J. Epidemiol., September 15, 2006; 164(6): 556 - 566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kim, N. Chongviriyaphan, C. Liu, R. M. Russell, and X.-D. Wang Combined antioxidant ({beta}-carotene, {alpha}-tocopherol and ascorbic acid) supplementation increases the levels of lung retinoic acid and inhibits the activation of mitogen-activated protein kinase in the ferret lung cancer model Carcinogenesis, July 1, 2006; 27(7): 1410 - 1419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Liu, R. M. Russell, and X.-D. Wang Lycopene Supplementation Prevents Smoke-Induced Changes in p53, p53 Phosphorylation, Cell Proliferation, and Apoptosis in the Gastric Mucosa of Ferrets J. Nutr., January 1, 2006; 136(1): 106 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-Y. Zhong, Y.-M. Zhou, G. C. Douglas, H. Witschi, and K. E. Pinkerton MAPK/AP-1 signal pathway in tobacco smoke-induced cell proliferation and squamous metaplasia in the lungs of rats Carcinogenesis, December 1, 2005; 26(12): 2187 - 2195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Mayne and S. M. Lippman Cigarettes: A Smoking Gun in Cancer Chemoprevention J Natl Cancer Inst, September 21, 2005; 97(18): 1319 - 1321. [Full Text] [PDF]
|
|
|
|
|
|
S. S. Hecht Carcinogenicity studies of inhaled cigarette smoke in laboratory animals: old and new Carcinogenesis, September 1, 2005; 26(9): 1488 - 1492. [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]
|
|
|
|
|
|
E. S. Fiala, O. S. Sohn, C.-X. Wang, E. Seibert, J. Tsurutani, P. A. Dennis, K. El-Bayoumy, R. S. Sodum, D. Desai, J. Reinhardt, et al. Induction of preneoplastic lung lesions in guinea pigs by cigarette smoke inhalation and their exacerbation by high dietary levels of vitamins C and E Carcinogenesis, March 1, 2005; 26(3): 605 - 612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Serrano, L. Baglietto, H. Johansson, F. Mariette, R. Torrisi, M. Onetto, M. Paganuzzi, and A. Decensi Effect of the Synthetic Retinoid Fenretinide on Circulating Free Prostate-Specific Antigen, Insulin-Like Growth Factor-I, and Insulin-Like Growth Factor Binding Protein-3 Levels in Men with Superficial Bladder Cancer Clin. Cancer Res., March 1, 2005; 11(5): 2083 - 2088. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Zhang, P. Adiseshaiah, and S. P. Reddy Matrix Metalloproteinase/Epidermal Growth Factor Receptor/Mitogen-Activated Protein Kinase Signaling Regulate fra-1 Induction by Cigarette Smoke in Lung Epithelial Cells Am. J. Respir. Cell Mol. Biol., January 1, 2005; 32(1): 72 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Goodman, M. D. Thornquist, J. Balmes, M. R. Cullen, F. L. Meyskens Jr., G. S. Omenn, B. Valanis, and J. H. Williams Jr. The Beta-Carotene and Retinol Efficacy Trial: Incidence of Lung Cancer and Cardiovascular Disease Mortality During 6-Year Follow-up After Stopping {beta}-Carotene and Retinol Supplements J Natl Cancer Inst, December 1, 2004; 96(23): 1743 - 1750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Liu, R. M. Russell, and X.-D. Wang Low Dose {beta}-Carotene Supplementation of Ferrets Attenuates Smoke-Induced Lung Phosphorylation of JNK, p38 MAPK, and p53 Proteins J. Nutr., October 1, 2004; 134(10): 2705 - 2710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Palozza, S. Serini, F. Di Nicuolo, A. Boninsegna, A. Torsello, N. Maggiano, F. O. Ranelletti, F. I. Wolf, G. Calviello, and A. Cittadini {beta}-Carotene exacerbates DNA oxidative damage and modifies p53-related pathways of cell proliferation and apoptosis in cultured cells exposed to tobacco smoke condensate Carcinogenesis, August 1, 2004; 25(8): 1315 - 1325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Wright, S. T. Mayne, R. Z. Stolzenberg-Solomon, Z. Li, P. Pietinen, P. R. Taylor, J. Virtamo, and D. Albanes Development of a Comprehensive Dietary Antioxidant Index and Application to Lung Cancer Risk in a Cohort of Male Smokers Am. J. Epidemiol., July 1, 2004; 160(1): 68 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. S. Kleinjans, M. H. M. van Herwijnen, J. M. S. van Maanen, L. M. Maas, T. M. C. M. de Kok, H. J. J. Moonen, and J. J. Briede In vitro investigations into the interaction of {beta}-carotene with DNA: evidence for the role of carbon-centered free radicals Carcinogenesis, July 1, 2004; 25(7): 1249 - 1256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Omenn Human Lung Cancer Chemoprevention Strategies: Parker B. Francis Lecture Chest, May 1, 2004; 125(5_suppl): 123S - 127S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Prakash, C. Liu, K.-Q. Hu, N. I. Krinsky, R. M. Russell, and X.-D. Wang {beta}-Carotene and {beta}-Apo-14'-Carotenoic Acid Prevent the Reduction of Retinoic Acid Receptor {beta} in Benzo[a]pyrene-Treated Normal Human Bronchial Epithelial Cells J. Nutr., March 1, 2004; 134(3): 667 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Winterhalder, F. R. Hirsch, G. K. Kotantoulas, W. A. Franklin, and P. A. Bunn Jr Chemoprevention of lung cancer--from biology to clinical reality Ann. Onc., February 1, 2004; 15(2): 185 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Liu, R. M. Russell, and X.-D. Wang {alpha}-Tocopherol and Ascorbic Acid Decrease the Production of {beta}-Apo-carotenals and Increase the Formation of Retinoids from {beta}-Carotene in the Lung Tissues of Cigarette Smoke-Exposed Ferrets In Vitro J. Nutr., February 1, 2004; 134(2): 426 - 430. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Russell The Enigma of {beta}-Carotene in Carcinogenesis: What Can Be Learned from Animal Studies J. Nutr., January 1, 2004; 134(1): 262S - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Li, A. Molteni, P. Latkovich, W. Castellani, and R. C. Baybutt Vitamin A Depletion Induced by Cigarette Smoke Is Associated with the Development of Emphysema in Rats J. Nutr., August 1, 2003; 133(8): 2629 - 2634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 The ATBC Study Group Incidence of Cancer and Mortality Following {alpha}-Tocopherol and {beta}-Carotene Supplementation: A Postintervention Follow-up JAMA, July 23, 2003; 290(4): 476 - 485. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Liu, F. Lian, D. E. Smith, R. M. Russell, and X.-D. Wang Lycopene Supplementation Inhibits Lung Squamous Metaplasia and Induces Apoptosis via Up-Regulating Insulin-like Growth Factor-binding Protein 3 in Cigarette Smoke-exposed Ferrets Cancer Res., June 15, 2003; 63(12): 3138 - 3144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Goodman, S. Schaffer, G. S. Omenn, C. Chen, and I. King The Association between Lung and Prostate Cancer Risk, and Serum Micronutrients: Results and Lessons Learned from {beta}-Carotene and Retinol Efficacy Trial Cancer Epidemiol. Biomarkers Prev., June 1, 2003; 12(6): 518 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Baron, B. F. Cole, L. Mott, R. Haile, M. Grau, T. R. Church, G. J. Beck, and E. R. Greenberg Neoplastic and Antineoplastic Effects of {beta}-Carotene on Colorectal Adenoma Recurrence: Results of a Randomized Trial J Natl Cancer Inst, May 21, 2003; 95(10): 717 - 722. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Neuhouser, R. E. Patterson, M. D. Thornquist, G. S. Omenn, I. B. King, and G. E. Goodman Fruits and Vegetables Are Associated with Lower Lung Cancer Risk Only in the Placebo Arm of the {beta}-Carotene and Retinol Efficacy Trial (CARET) Cancer Epidemiol. Biomarkers Prev., April 1, 2003; 12(4): 350 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Liu, R. M. Russell, and X.-D. Wang Exposing Ferrets to Cigarette Smoke and a Pharmacological Dose of {beta}-Carotene Supplementation Enhance In Vitro Retinoic Acid Catabolism in Lungs via Induction of Cytochrome P450 Enzymes J. Nutr., January 1, 2003; 133(1): 173 - 179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. M. Reddy and B. T. Mossman Role and regulation of activator protein-1 in toxicant-induced responses of the lung Am J Physiol Lung Cell Mol Physiol, December 1, 2002; 283(6): L1161 - L1178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. C. Obermueller-Jevic, I. Espiritu, A. M. Corbacho, C. E. Cross, and H. Witschi Lung Tumor Development in Mice Exposed to Tobacco Smoke and Fed {beta}-Carotene Diets Toxicol. Sci., September 1, 2002; 69(1): 23 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Wolf The effect of {beta}-carotene on lung and skin carcinogenesis Carcinogenesis, August 1, 2002; 23(8): 1263 - 1265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Witschi, I. Espiritu, M. Suffia, and K. E. Pinkerton Expression of cyclin D1/2 in the lungs of strain A/J mice fed chemopreventive agents Carcinogenesis, February 1, 2002; 23(2): 289 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Omenn RESPONSE: Chemoprevention or Antichemo- prevention? A Salutary Warning From the {beta}-Carotene Experience J Natl Cancer Inst, July 18, 2001; 93(14): 1111 - 1111. [Full Text] [PDF]
|
|