title: Effects of physiological versus pharmacological beta-carotene supplementation on cell proliferation and histopathological changes in the lungs of cigarette smoke-exposed ferrets.
abstract: There remains a remarkable discordance between the results of observational epidemiological studies and intervention trials using beta-carotene as a potential chemopreventive agent. One question that needs to be examined is whether the adverse outcomes of human beta-carotene trials are related to the large doses of beta-carotene that were administered. In the present study, ferrets were given a physiological (low) dose or a pharmacological (high) dose of beta-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 beta-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 beta-carotene (LBC), high-dose beta-carotene (HBC), low-dose beta-carotene plus smoke exposure (LBC+SM) or high-dose beta-carotene plus smoke exposure (HBC+SM)-for 6 months. Retinoic acid concentration and RAR beta gene expression, but not expression of RAR alpha and RAR gamma, 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 beta-carotene, a physiological dose of beta-carotene in smoke-exposed ferrets has no potentially detrimental effects and may afford weak protection against lung damage induced by cigarette smoke.
authors.affiliation: Jean Mayer United States Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: X D
authors.initials: XD
authors.lastname: Wang
authors.forename: R T
authors.initials: RT
authors.lastname: Bronson
authors.forename: D E
authors.initials: DE
authors.lastname: Smith
authors.forename: N I
authors.initials: NI
authors.lastname: Krinsky
authors.forename: R M
authors.initials: RM
authors.lastname: Russell
mesh_terms: D000818:Animals; D002455:Cell Division; D019938:Cyclin D1 / Q000032:analysis; D019587:Dietary Supplements; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis; D000084562:Retinyl Esters; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D014212:Tretinoin / Q000097:blood / Q000378:metabolism; D014801:Vitamin A / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D019207:beta Carotene / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004224:Diterpenes; D018809:Proliferating Cell Nuclear Antigen; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D000084562:Retinyl Esters; D014028:Tobacco Smoke Pollution; D019207:beta Carotene; D014801:Vitamin A; D019938:Cyclin D1; C014794:retinol palmitate; D014212:Tretinoin