Combined alpha‐tocopherol and ascorbic acid supplementation suppresses smoke‐induced lung squamous metaplasia in ferrets by preventing retinoic acid reduction

Abstract

Previously we demonstrated that cigarette smoke exposure (CSE)-induced lung lesions in ferrets were prevented by a combination of low dose of β-carotene, α-tocopherol (AT), and ascorbic acid (AA). However, the role of a combination of AT and AA alone in the protective effect on lung carcinogenesis remains to be examined. In the present study, we investigated whether the combined AT (equivalent to ~100 mg/day in the human) and AA (equivalent to ~210 mg/day) supplementation prevents against CSE (equivalent to 1.5 packs of cigarettes/day) induced lung squamous metaplasia in ferrets. Ferrets were treated for 6 weeks in the following three groups (9 ferrets/group): (i) Control (no CSE, no AT+AA), (ii) CSE, and (iii) CSE+AT+AA. Result showed that CSE significantly decreased concentrations of retinoic acid, AT, and reduced form of AA, not total AA and retinol, in the lungs of ferrets. Combined AT+AA treatment not only increased levels of AT and reduced AA, but also restored the lower concentration of retinoic acid in the lungs of CSE-exposed ferrets to normal levels as the control group. Furthermore, the combined AT+AA supplementation prevented CSE-induced squamous metaplasia and cyclin D1 expression in the lungs. Using HPLC analysis, we were unable to detect any difference on lung microsomal thiobarbituric acid-malondialdehyde levels among the three groups. These data indicate that the combination of AT+AA alone exerts protective effects against CSE-induced lung lesions by restoring retinoic acid levels to normal. This result could be due to their potential to prevent CSE-induced retinoid acid degradation. (Supported by NIH grant R01CA104932 and USDA grant 1950-51000-064).