Safety, Tolerability, and Pharmacokinetics of β-Cryptoxanthin Supplementation in Healthy Women: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial

Abstract

Background: β-cryptoxanthin is a dietary carotenoid for which there have been few studies on the safety and pharmacokinetics following daily oral supplementation.

Methods: 90 healthy Asian women between 21 and 35 years were randomized into three groups: 3 and 6 mg/day oral β-cryptoxanthin, and placebo. At 2, 4, and 8 weeks of supplementation, plasma carotenoid levels were measured. The effects of β-cryptoxanthin on blood retinoid-dependent gene expression, mood, physical activity and sleep, metabolic parameters, and fecal microbial composition were investigated.

Results: β-cryptoxanthin supplementation for 8 weeks (3 and 6 mg/day) was found to be safe and well tolerated. Plasma β-cryptoxanthin concentration was significantly higher in the 6 mg/day group (9.0 ± 4.1 µmol/L) compared to 3 mg/day group (6.0 ± 2.6 µmol/L) (p < 0.03), and placebo (0.4 ± 0.1 µmol/L) (p < 0.001) after 8 weeks. Plasma all-trans retinol, α-cryptoxanthin, α-carotene, β-carotene, lycopene, lutein, and zeaxanthin levels were not significantly changed. No effects were found on blood retinol-dependent gene expression, mood, physical activity and sleep, metabolic parameters, and fecal microbial composition.

Conclusions: Oral β-cryptoxanthin supplementation over 8 weeks lead to high plasma concentrations of β-cryptoxanthin, with no impact on other carotenoids, and was well tolerated in healthy women.

Keywords: Asian women; carotenoids; fecal microbiome; gene expression; mood; physical activity.

Figure 1

Flowchart of study visits.

Figure 2

Flowchart of participants.

Figure 3

Time-course of plasma carotenoid concentrations. Mean plasma carotenoid concentrations in (µmol/L) ± standard error of the mean are shown at weeks 0, 2, 4, and 8. The placebo group is represented with blue lines, the 3 mg β-cryptoxanthin group is represented with red lines, and the 6 mg β-cryptoxanthin group is represented with green lines. (A) β-cryptoxanthin, (B) α-cryptoxanthin, (C) all-trans retinol, (D) lutein, (E) zeaxanthin, (F) lycopene, (G) α-carotene, and (H) β-carotene.

Figure 4

Fold changes of retinol-dependent gene expression in peripheral blood mononuclear cells from placebo and β-cryptoxanthin supplementation groups. Fold changes in gene expression from baseline to week 8 were calculated using normalized Cq values. Values are expressed as mean ± standard deviation. Dose of β-cryptoxanthin in mg per day is indicated on the x-axis. (A) RARA, (B) RXRA, (C) RXRB, (D) BHLHE40, (E) PPARD, and (F) ALDH1A1.

Figure 5

Alpha diversity of the gut microbial community in 3 different treatment groups before and after supplementation. (A) Shannon entropy. (B) Pielou’s evenness. All the data were expressed with Tukey style boxplots. The dots represent outliers. A1: 3 mg/day β-cryptoxanthin at baseline, A2: 3 mg/day β-cryptoxanthin after 8 weeks, B1: 6 mg/day β-cryptoxanthin at baseline, B2: 6 mg/day β-cryptoxanthin after 8 weeks, C1: placebo at baseline, C2: placebo after 8 weeks.

Figure 6

Beta diversity of the gut microbial community in 3 different treatment groups before and after supplementation. Principal coordinate analysis based on (A) Bray-Curtis and (B) Weighted UniFrac distances. A1: 3 mg/day β-cryptoxanthin at baseline, A2: 3 mg/day β-cryptoxanthin after 8 weeks, B1: 6 mg/day β-cryptoxanthin at baseline, B2: 6 mg/day β-cryptoxanthin after 8 weeks, C1: placebo at baseline, C2: placebo after 8 weeks.