Fumiki Aoki

Suppression by Licorice Flavonoids of Abdominal Fat Accumulation and Body Weight Gain in High-Fat Diet-Induced Obese C57BL/6J Mice

We applied licorice flavonoid oil (LFO) to high-fat diet-induced obese C57BL/6J mice and investigated its effect. LFO contains hydrophobic flavonoids obtained from licorice by extraction with ethanol. The oil is a mixture of medium-chain triglycerides, having glabridin, a major flavonoid of licorice, concentrated to 1.2% (w/w). Obese mice were fed on a high-fat diet containing LFO at 0 (control), 0.5%, 1.0%, or 2.0% for 8 weeks. Compared with mice in the control group, those in the 1% and 2% LFO groups efficiently reduced the weight of abdominal white adipose tissues and body weight gain. A histological examination revealed that the adipocytes became smaller and the fatty degenerative state of the hepatocytes was improved in the 2% LFO group. A DNA microarray analysis of the liver showed up-regulation of those genes for beta-oxidation and down-regulation of those for fatty acid synthesis in the 2% LFO group. These findings suggest that LFO prevented and ameliorated diet-induced obesity via the regulation of lipid metabolism-related gene expression in the liver.

Clinical Safety of Licorice Flavonoid Oil (LFO) and Pharmacokinetics of Glabridin in Healthy Humans

Objective: Licorice flavonoids have various physiological activities such as abdominal fat-lowering, hypoglycemic and antioxidant effects. Licorice flavonoid oil (LFO: Kaneka Glavonoid Rich Oil™) is a new dietary ingredient containing licorice flavonoids dissolved in medium-chain triglycerides (MCT). Glabridin is one of the bioactive flavonoids included specifically in licorice Glycyrrhiza glabra L. and is the most abundant flavonoid in LFO. In this study, we assessed the safety of LFO in healthy humans and determined the plasma concentration profile of glabridin as a marker compound. Methods: A single-dose and two multiple-dose studies at low (300 mg), moderate (600 mg) and high (1200 mg) daily doses of LFO were carried out using a placebo-controlled single-blind design. In each study the safety of LFO and the pharmacokinetics of glabridin were assessed. Results: Pharmacokinetic analysis in the single-dose study with healthy male subjects (n = 5) showed that glabridin was absorbed and reached the maximum concentration (Cmax) after approximately 4 h (Tmax), and then eliminated relatively slowly in a single phase with a T1/2 of approximately 10 h at all doses. The Cmax and AUC0–24 h increased almost linearly with dose. The multiple-dose studies with healthy male and female subjects for 1 week and 4 weeks suggested that plasma glabridin reached steady state levels within 2 weeks with a single daily administration of 300 to 1200 mg/day LFO. In these human studies at three dose levels, there were no clinically noteworthy changes in hematological or related biochemical parameters. All clinical events observed were mild and considered to be unrelated to LFO administration even after repeated administration for 4 weeks. Conclusion: These studies demonstrated that LFO is safe when administered once daily up to 1200 mg/day. This is the first report on the safety of licorice flavonoids in an oil preparation and the first report on the pharmacokinetics of glabridin in human subjects.

Increased Bioavailability of Ubiquinol Compared to That of Ubiquinone Is Due to More Efficient Micellarization during Digestion and Greater GSH-Dependent Uptake and Basolateral Secretion by Caco-2 Cells

The oral bioavailability of ubiquinol recently has been reported to be greater than that of ubiquinone in healthy adults. The basis for this influence of redox state of coenzyme Q (CoQ) on bioavailability has been investigated using the coupled in vitro digestion/Caco-2 cell model. Solubilized ubiquinol and ubiquinone were added to yogurt and subjected to simulated gastric and small intestinal digestion. Partitioning of CoQ in mixed micelles during small intestinal digestion was significantly greater during digestion of yogurt enriched with ubiquinol. Similarly, apical uptake from mixed micelles and transepithelial transport of CoQ by Caco-2 cells were significantly greater after digestion of the ubiquinol-rich yogurt compared to digested ubiquinone-rich yogurt. Reduction of cellular GSH significantly decreased cell uptake and basolateral secretion of both ubiquinol and ubiquinone, although the adverse impact was much greater for ubiquinol. These data suggest that the enhanced bioaccessibility and bioavailability of ubiquinol compared to ubiquinone results from reduced coenzyme being more efficiently incorporated into mixed micelles during digestion and its greater uptake and basolateral secretion in a glutathione-dependent mechanism.