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Nutrient Interactions and Toxicity

Exposing Ferrets to Cigarette Smoke and a Pharmacological Dose of ß-Carotene Supplementation Enhance In Vitro Retinoic Acid Catabolism in Lungs via Induction of Cytochrome P450 Enzymes^1,2

Nutrition and Cancer Biology Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111

³To whom correspondence should be addressed. E-mail: xwang{at}hnrc.Tufts.edu

In our previous studies, we found lower levels of retinoic acid (RA) in the lungs of ferrets exposed to cigarette smoke and/or a pharmacological dose of ß-carotene. To determine whether this is involved in excessive catabolism of RA via cytochrome P450 (CYP) induction, we carried out in vitro incubations of RA with the lung microsomal fractions of ferrets with or without CYP inhibitors and antibodies against CYP. The polar metabolites (4-oxo-RA and 18-hydroxy-RA) of RA metabolism after the incubation were analyzed by HPLC. Expressions of CYP (1A1, 1A2, 2E1 and 3A1) were examined using Western blot analysis. Incubation of various concentrations of RA with the lung microsomal fraction from ferrets exposed to cigarette smoke, a pharmacological dose of ß-carotene or their combination dose-dependently increased the levels of 4-oxo-RA and 18-hydroxy-RA compared with that of the control ferrets. At all RA concentrations, this increase was the greatest in lung tissue from the combined treatment group. Furthermore, this enhanced RA catabolism was substantially (80%) inhibited by nonspecific CYP inhibitors (disulfiram and liarozole), but was partially (50%) inhibited by resveratrol (CYP1A1 inhibitor), -naphthoflavone (CYP1A2 inhibitor) and antibodies against CYP1A1 and CYP1A2. Cigarette smoke exposure and/or pharmacological doses of ß-carotene increased levels of CYP1A1 and 1A2 by three- to sixfold but not levels of 2E1 and 3A1 in ferret lung tissue. These findings suggest that low levels of RA in the lung of ferrets exposed to cigarette smoke and/or pharmacological doses of ß-carotene may be caused by the enhanced RA catabolism via induction of CYP, CYP1A1 and CYP1A2 in particular, which provides a possible explanation for enhanced lung carcinogenesis seen with pharmacological doses of ß-carotene supplementation in cigarette smokers.

KEY WORDS: • cigarette smoke • ß-carotene • cytochrome P450 • retinoic acid

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