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

Takashi Matsumoto,Yoshio Kase,Yousuke Matsubara,Hiroaki Nishimura,Tomohisa Hattori,Junko Watanabe,Atsushi Kaneko,Junichi Koseki,Kazuya Maemura,Kazuaki Tsuchiya,Kyoji Sekiguchi,Yasuharu Mizuhara

doi:10.3390/molecules201018031

Takashi Matsumoto, Yoshio Kase + Show 10 more

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https://doi.org/10.3390/molecules201018031

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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.

Highlights

Most orally administered polyphenols are metabolized in a living body
Rats subjected to intradermal injection of P. acnes and orally administered distilled water developed rapid ear swelling with cutaneous erythema, followed by a 181% increase in ear thickness in a 24 h period compared with that prior to injection (Figure 1)
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

Summary

Introduction

Most orally administered polyphenols are metabolized in a living body. Flavonoids are known to undergo conjugation in the intestine and liver and circulate predominantly as glucuronides and sulfates with very little as aglycones and/or unchanged forms [1,2,3,4]. It is important to elucidate the metabolism and plasma pharmacokinetics of polyphenols in a study focusing on diseases of the nondigestive organs such as skin. JHT is reportedly effective in patients with inflammatory acne [9], and inhibited hapten-induced inflammation in a mouse model of allergic dermatitis [10]. We recently reported that JHT inhibited increases in ear thickness in two models of acute dermatitis developed using phorbol myristate acetate or Propionibacterium acnes (P. acnes), a gram-positive anaerobic microbe [11]. To investigate the potential mechanism of JHT, we examined antioxidant activities of the crude drugs and constituents, demonstrating that polyphenols originating from Quercus cortex (Q. cortex), Schizonepetae spica (S. spica), and Glycyrrhizae radix (G. radix) were active in an assay focusing on antioxidant activity against reactive oxygen species (ROS)

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