Metabolome Analysis Reveals Dermal Histamine Accumulation in Murine Dermatitis Provoked by Genetic Deletion of P-Glycoprotein and Breast Cancer Resistance Protein

Naoto Hashimoto, Noritaka Nakamichi, Hikari Nanmo, Kei ichi Kimura, Yusuke Masuo, Yasuyuki Sakai, Alfred H. Schinkel, Shinichi Sato, Tomoyoshi Soga, Yukio Kato

Research output: Contribution to journalArticle

Abstract

Purpose: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are xenobiotic transporters which pump out variety types of compounds, but information on their interaction with endogenous substrates in the skin is limited. The purpose of the present study was to clarify possible association of these transporters in dermal accumulation of inflammatory mediators. Methods: Dermatitis model was constructed by repeated topical application of oxazolone in wild-type, and P-gp and BCRP gene triple knockout (Mdr1a/1b/Bcrp−/−) mice to observe difference in phenotype. Target metabolome analysis of 583 metabolites was performed using skin and plasma. Results: Dermatitis and scratching behavior in dermatitis model of Mdr1a/1b/Bcrp−/− mice were more severe than wild-type mice, suggesting protective roles of these transporters. This hypothesis was supported by the metabolome analysis which revealed that concentration of histamine and other dermatitis-associated metabolites like urate and serotonin in the dermatitis skin, but not normal skin, of Mdr1a/1b/Bcrp−/− mice was higher than that of wild-type mice. Gene expression of P-gp and BCRP was reduced in oxazolone-treated skin and the skin of patients with atopic dermatitis or psoriasis. Conclusions: These results suggest possible association of these efflux transporters with dermal inflammatory mediators, and such association could be observed in the dermatitis skin.

Original languageEnglish
Article number158
JournalPharmaceutical research
Volume36
Issue number11
DOIs
Publication statusPublished - 2019 Nov 1

Keywords

  • P-glycoprotein
  • breast cancer resistance protein
  • dermatitis
  • histamine
  • metabolomics

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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