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United States Department of Agriculture

Agricultural Research Service

Title: Cigarette Smoke-Exposure and Pharmacological Dose Beta-Carotene Supplementation Enhance Retinoic Acid Catabolism Via Induction of Cytochrome P450 Enzymes in Lung of Ferrets

Authors
item Liu, Chun - HNRCA
item Russell, Robert - HNRCA
item Wang, Xiang-Dong - HNRCA

Submitted to: Carotenoid Symposium
Publication Type: Abstract Only
Publication Acceptance Date: October 15, 2001
Publication Date: January 6, 2002
Citation: LIU, C., RUSSELL, R.M., WANG, X. CIGARETTE SMOKE-EXPOSURE AND PHARMACOLOGICAL DOSE BETA-CAROTENE SUPPLEMENTATION ENHANCE RETINOIC ACID CATABOLISM VIA INDUCTION OF CYTOCHROME P450 ENZYMES IN LUNG OF FERRETS. INTERNATIONAL CAROTENOID SYMPOSIUM. 2002;94.

Technical Abstract: In our previous studies, the concentrations of retinoic acid (RA) and the expression of RA receptor beta in lung tissue were significantly lower in the ferrets treated with cigarette smoke-exposure, pharmacological dose beta-carotene, but not physiological dose beta-carotene. In order to determine whether the lower level of RA in the ferret lung after smoke or pharmacological dose beta-carotene treatment for six month is involved in excess catabolism of RA into polar metabolites via cytochrome P450 (CYP) induction, in vitro incubation of RA with the microsome fractions of ferret lung with or without CYP chemical inhibitors was carried out. The polar metabolites (18-hydroxy-RA and 4-oxo-RA) of RA metabolism after the incubation were extracted and analyzed by HPLC. Induction of CYPs (1A1/2, 2E1 and 3A1) was examined using Western blot analysis. We found that incubation of RA with the lung microsomal fraction from either smoke exposed and pharmacological dose beta-carotene supplemented ferrets resulted in greater disappearance of RA and increased appearance of 18-hydroxy-RA and 4-oxo-RA, as compared with the control and physiological dose beta-carotene supplemented ferrets. Both smoke-exposure and pharmacological dose beta-carotene supplementation to ferrets increased lung tissue levels of CYP1A1/2, but not 2E1 and 3A1. Furthermore, the enhancement of RA catabolism by smoke-exposure and pharmacological dose beta-carotene supplementation were inhibited almost completely by non-specific CYP inhibitors (disulfiram and liarozole) in a dose-dependent fashion, but were only partially inhibited by chemical inhibitors (resveratrol and alpha-naphthoflvone) and antibody against CYP1A1. These findings indicate that low levels of RA in the lung of ferrets after either smoke-exposure, pharmacological dose beta-carotene supplementation, or both may be in part caused by enhancement of retinoic acid catabolism via induction of CYPs, which provides a possible explanation for enhancing lung carcinogenesis of pharmacological dose beta-carotene supplementation in cigarette smokers. (Supported by ACS grant#RSG-01-030-01-CNE and BASF)

Last Modified: 9/10/2014
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