Metabolome Analysis Reveals Dermal Histamine Accumulation in Murine Dermatitis Provoked by Genetic Deletion of P-Glycoprotein and Breast Cancer Resistance Protein
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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 Wordsbreast cancer resistance protein dermatitis histamine metabolomics P-glycoprotein
Acidic ribosomal phosphoprotein P0
Breast cancer resistance protein
Capillary electrophoresis with time-of-flight mass spectrometry
Glyceraldehyde 3-phosphate dehydrogenase
Hanks’ balanced salt solution
High-performance liquid chromatography/tandem mass spectrometry
- MDCK II
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).