Metabolomic profile of response to supplementation with β-carotene in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

Background: Two chemoprevention trials found that supplementation with b-carotene increased the risk of lung cancer and overall mortality. The biologic basis of these findings remains poorly understood. Objective: The objective was to compare the on-study change in metabolomic profiles of men randomly assigned to receive or not receive b-carotene supplements in the Alpha-Tocopherol, BetaCarotene Cancer Prevention (ATBC) Study. Design: The ATBC Study was a randomized, double-blind, placebo-controlled, primary cancer prevention trial; participants were Finnish male smokers assigned to 1 of 4 intervention groups: 1) a-tocopherol, 2) b-carotene, 3) both, or 4) placebo. Fifty participants with both baseline and follow-up fasting serum samples were randomly selected from each of these groups. Metabolomic profiling was conducted by mass spectrometry. The association between change in each metabolite over time and trial assignment (b-carotene or no b-carotene) was estimated by linear regression. Results: We measured 489 metabolites, and 17 changed significantly (P , 0.05) in response to b-carotene supplementation. More of these 17 metabolites were of xenobiotic origin than would be expected by chance (9 of 60, or 15%; P = 0.00004). We also found a suggestive association with 1,5-anhydroglucitol—a marker of glycemic control (b = 20.379, P = 0.0071). Conclusions: Male smokers supplemented with b-carotene developed metabolomic profiles consistent with the induction of cytochrome P450 enzymes, the primary metabolizers of xenobiotics in humans. These findings may shed light on the increased mortality associated with b-carotene supplementation in the ATBC Study and suggest the need to explore potential interactions between medication use and dietary supplements, particularly among smokers. This trial was registered at clinicaltrials.gov as NCT00342992. Am J Clin Nutr 2013;98:488‐93.