Reduction in plasma or skin alpha-tocopherol concentration with long-term oral administration of beta-carotene in humans and mice

Abstract

Background: Beta-carotene is one of the most commonly used compounds in clinical trials of chemopreventive agents in various neoplastic diseases. Animal studies, including our own, have documented that dietary beta-carotene can reduce plasma alpha-tocopherol (vitamin E) levels, but few published studies have examined the clinical or pharmacokinetic ramifications of long-term, high-dose beta-carotene regimens on other fat-soluble vitamins such as alpha-tocopherol.

Purpose: This study was designed to determine the effects of long-term beta-carotene supplementation on plasma concentrations of alpha-tocopherol in normal human subjects and in an experimental C3H/HeN mouse model.

Methods: In a double-blind study, 45 normal subjects were randomly assigned to receive 0 (placebo), 15, 30, 45, or 60 mg of oral beta-carotene daily for approximately 9 months. Monthly plasma samples were collected. Thirty-five C3H/HeN mice were fed a basal diet with or without beta-carotene and treated topically with or without alpha-tocopherol, except for the control mice, which received UV radiation for 27 weeks from week 3 to week 30. Plasma and dorsal skin samples were taken after 40 weeks and were analyzed for alpha-tocopherol and/or beta-carotene by high-performance liquid chromatography.

Results: Long-term dietary beta-carotene administration resulted in statistically significant reductions in levels of alpha-tocopherol in the skin and plasma of UV-irradiated mice. In the human study, the decrease in plasma alpha-tocopherol levels was progressive and significant between 6 and 9 months of beta-carotene dosing in all dosage groups. The greatest decrease was observed during the 9th (last) month of dosing, with a decrease of 40% from baseline. All oral beta-carotene doses (15-60 mg/d), however, resulted in similar decreases in steady-state plasma levels of alpha-tocopherol and in only small differences in beta-carotene plasma levels.

Conclusion: Long-term oral administration of beta-carotene decreased steady-state plasma concentrations of alpha-tocopherol. The lack of a significant dose-response effect between doses of beta-carotene and alpha-tocopherol plasma levels is not unexpected, given the small differences in steady-state beta-carotene plasma levels in the four beta-carotene dose groups.

Implications: Studies are needed to determine how long-term beta-carotene dosing influences tissue distribution of dietary alpha-tocopherol. Careful surveillance for this and other potentially harmful nutrient interactions should become part of all long-term intervention studies.