Abstract
Recent studies have demonstrated that flavonoid glucuronides can be deconjugated to the active form aglycone by β-glucuronidase-expressing macrophages. Keigairengyoto (KRT) is a flavonoid-rich traditional Japanese medicine reported to enhance bacterial clearance through immune modulation. Our aims are to examine the pharmacokinetics of KRT flavonoids and to identify active flavonoids contributing to the adjuvant effects of KRT. KRT was evaluated at pharmacokinetic analysis to quantify absorbed flavonoids, and cutaneous infection assay induced in mice by inoculation of Staphylococcus aureus. Preventive or therapeutic KRT administration reduced the number of bacteria in the infection site as well as macroscopic and microscopic lesion scores with efficacies similar to antibiotics. Pharmacokinetic study revealed low plasma levels of flavonoid aglycones after KRT administration; however, plasma concentrations were enhanced markedly by β-glucuronidase treatment, with baicalein the most abundant (Cmax, 1.32 µg/mL). In random screening assays, flavonoids such as bacalein, genistein, and apigenin enhanced bacteria phagocytosis by macrophages. Glucuronide bacalin was converted to aglycone baicalein by incubation with living macrophages, macrophage lysate, or skin homogenate. Taken together, the adjuvant effect of KRT may be due to some blood-absorbed flavonoids which enhance macrophage functions in host defense. Flavonoid-rich KRT may be a beneficial treatment for infectious skin inflammation.
Highlights
Flavonoids are promising bioactive agents against cancer, inflammatory disease, cardiovascular disease, neurological disorders, metabolic syndrome, obesity, and osteoporosis [1,2,3,4], and epidemiological studies show that consumption of flavonoid-rich foods is associated with reduced risks of cancer and cardiovascular disease [5,6]
We reported that oral administration of KRT suppressed microbe-induced dermatosis in suppressed microbe-induced dermatosis in mice and enhanced bacterial clearance through mice and enhanced bacterial clearance through modulation of the immune system
This study revealed that glucuronides of baicalein, wogonin, liquiritigenin, and genistein were largely increased in plasma from 2 to 10 h after KRT administration
Summary
Flavonoids are promising bioactive agents against cancer, inflammatory disease, cardiovascular disease, neurological disorders, metabolic syndrome, obesity, and osteoporosis [1,2,3,4], and epidemiological studies show that consumption of flavonoid-rich foods is associated with reduced risks of cancer and cardiovascular disease [5,6]. Clinical and experimental studies of individual flavonoids such as baicalin, genistein, and tea catechin have reported such efficacies [7,8,9,10,11]. Flavonoids are converted to inactive metabolites like glucuronides in the gut, and circulate mainly as glucuronides in the blood stream, resulting in low concentrations of circulating active aglycones [12,13,14]. It is unclear how oral flavonoids exert bioactivity in tissues, an issue termed “the flavonoid paradox”.
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