Pharmaceutical Research

, 36:158 | Cite as

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 KatoEmail author
Research Paper



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.


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.


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.


These results suggest possible association of these efflux transporters with dermal inflammatory mediators, and such association could be observed in the dermatitis skin.

Key Words

breast cancer resistance protein dermatitis histamine metabolomics P-glycoprotein 



Acidic ribosomal phosphoprotein P0


Breast cancer resistance protein


Capillary electrophoresis with time-of-flight mass spectrometry


Electrospray ionization


Glyceraldehyde 3-phosphate dehydrogenase


Hanks’ balanced salt solution


Histidine decarboxylase


Histamine N-methyltransferase


High-performance liquid chromatography/tandem mass spectrometry


Mass-to-charge ratios


Monoamine oxidase


Madin-Darby canine kidney II


Multidrug resistance 1


Organic cation transporter.




Real-time polymerase chain reaction


Acknowledgments and Disclosures

We thank Mr. Kyosuke Shinoda (Laboratory of Molecular Pharmacotherapeutics, Kanazawa University, Japan) for performing transporter studies. This study was supported in part by Grant-in-Aids for Scientific Research to YK (25670011) and NN (No. 16 K08266) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and YK (S2601) from Japan Society for the Promotion of Science (JSPS).

Supplementary material

11095_2019_2695_MOESM1_ESM.docx (582 kb)
ESM 1 (DOCX 582 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Naoto Hashimoto
    • 1
    • 2
  • Noritaka Nakamichi
    • 1
  • Hikari Nanmo
    • 1
  • Kei-ichi Kimura
    • 3
  • Yusuke Masuo
    • 1
  • Yasuyuki Sakai
    • 4
  • Alfred H. Schinkel
    • 5
  • Shinichi Sato
    • 6
  • Tomoyoshi Soga
    • 7
  • Yukio Kato
    • 1
    Email author
  1. 1.Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
  2. 2.Drug Development Research Laboratories, Drug Metabolism and Pharmacokinetic Research DivisionMaruho Company Ltd.KyotoJapan
  3. 3.Department of Bioengineering, Graduate School of EngineeringUniversity of TokyoTokyoJapan
  4. 4.Department of Chemical System Engineering, Graduate School of EngineeringUniversity of TokyoTokyoJapan
  5. 5.The Netherlands Cancer InstituteAmsterdamThe Netherlands
  6. 6.Department of Dermatology, Graduate School of MedicineUniversity of TokyoTokyoJapan
  7. 7.Institute for Advanced BiosciencesKeio UniversityTsuruokaJapan

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