Plasma Pharmacokinetics of Polyphenols in a Traditional Japanese Medicine, Jumihaidokuto, Which Suppresses Propionibacterium acnes-Induced Dermatitis in Rats - PubMed (original) (raw)

. 2015 Sep 30;20(10):18031-46.

doi: 10.3390/molecules201018031.

Yousuke Matsubara 2, Yasuharu Mizuhara 3, Kyoji Sekiguchi 4, Junichi Koseki 5, Kazuaki Tsuchiya 6, Hiroaki Nishimura 7, Junko Watanabe 8, Atsushi Kaneko 9, Kazuya Maemura 10, Tomohisa Hattori 11, Yoshio Kase 12

Affiliations

Plasma Pharmacokinetics of Polyphenols in a Traditional Japanese Medicine, Jumihaidokuto, Which Suppresses Propionibacterium acnes-Induced Dermatitis in Rats

Takashi Matsumoto et al. Molecules. 2015.

Abstract

Most orally administered polyphenols are metabolized, with very little absorbed as aglycones and/or unchanged forms. Metabolic and pharmacokinetic studies are therefore necessary to understand the pharmacological mechanisms of polyphenols. Jumihaidokuto (JHT), a traditional Japanese medicine, has been used for treatment of skin diseases including inflammatory acne. Because JHT contains various types of bioactive polyphenols, our aim was to clarify the metabolism and pharmacokinetics of the polyphenols in JHT and identify active metabolites contributing to its antidermatitis effects. Orally administered JHT inhibited the increase in ear thickness in rats induced by intradermal injection of Propionibacterium acnes. Quantification by LC-MS/MS indicated that JHT contains various types of flavonoids and is also rich in hydrolysable tannins, such as 1,2,3,4,6-penta-O-galloyl glucose. Pharmacokinetic and antioxidant analyses showed that some flavonoid conjugates, such as genistein 7-O-glucuronide and liquiritigenin 7-O-glucuronide, appeared in rat plasma and had an activity to inhibit hydrogen peroxide-dependent oxidation. Furthermore, 4-O-methylgallic acid, a metabolite of Gallic acid, appeared in rat plasma and inhibited the nitric oxide reaction. JHT has numerous polyphenols; it inhibited dermatitis probably via the antioxidant effect of its metabolites. Our study is beneficial for understanding in vivo actions of orally administered polyphenol drugs.

Keywords: Gallic acid; antioxidant; dermatitis; flavonoid; genistein; glucuronides; jumihaidokuto; liquiritigenin; pharmacokinetics; tannin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Suppression of _Propionibacterium acnes (P. acnes)_-induced dermatitis in rats by jumihaidokuto (JHT) administration. Dermatitis was induced in rats by injection of P. acnes (0.14 mg/50 μL/ear) into the pinna. The ear thickness was measured at 0 and 24 h after the injection. JHT suspended in distilled water (DW) was administered orally at a dose of 0.5 g/10 mL/kg at 1 h before and 6 h after the injection. Prednisolone (PDN, 10 mg/10 mL/kg) was used as a reference drug. Data represent the relative ear thickness, which was standardized against the previous values before the injection. N = 5. ## p < 0.01 vs. saline + DW group (Student’s _t_-test), ** p < 0.01 significant vs. P. acnes + DW group (Dunnett’s test).

Figure 2

Figure 2

Plasma concentrations of jumihaidokuto (JHT) polyphenols in plasma before and after enzymatic hydrolysis with β-glucuronidase. Plasma samples were obtained at 1, 6, and 24 h after JHT administration to rats (2 g/10 mL/kg). The polyphenol content in the plasma were measured by LC-MS/MS before and after β-glucuronidase treatment. Each data point represents the mean ± S.E. of triplicates.

Figure 3

Figure 3

Time course of flavonoid glucuronides in the plasma of JHT-treated rats. Glucuronides of liquiritigenin, isoliquiritigenin, genistein, and hesperetin were measured in the plasma after JHT administration by LC-MS/MS. Each data point represents the mean ± S.E. of triplicates.

Figure 4

Figure 4

Concentration dependency of flavonoid glucuronides and comparison with aglycones. Glucuronides and aglycones of flavonoid were assayed at serially-diluted concentrations to assess on hydrogen peroxide-dependent oxidation. Test samples were incubated with hydrogen peroxide for 5 min, followed by mixing with a probe of oxidant activity. After 15 min incubation, the hydrogen peroxide-dependent fluorescent intensity was measured. Data are shown as mean ± S.E. of triplicates.

Figure 5

Figure 5

Chemical structures of metabolites appearing in plasma.

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