Metabolome Analysis Reveals Dermal Histamine Accumulation in Murine Dermatitis Provoked by Genetic Deletion of P-Glycoprotein and Breast Cancer Resistance Protein
Metabolome Analysis Reveals Dermal Histamine Accumulation in Murine Dermatitis Provoked by Genetic Deletion of P-Glycoprotein and Breast Cancer Resistance Protein
复制标题
DOI：
10.1007/s11095-019-2695-3
复制
发表时间：
2019-11-01
影响因子：
3.7
通讯作者：
Kato, Yukio
中科院分区：
文献类型：
--
作者：
Hashimoto, Naoto;Nakamichi, Noritaka;Kato, Yukio
目的P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）是外源性物质的转运蛋白，可泵出多种化合物，但关于它们与皮肤内源性底物相互作用的研究还很有限。本研究的目的是阐明这些转运蛋白在炎症介质真皮蓄积中的可能联系。方法采用口恶唑酮重复外用法建立野生型、P-gp和BCRP基因三重敲除（Mdr 1a/1b/Bcrp（-/-））小鼠模型，观察其表型差异。使用皮肤和血浆对583种代谢物进行靶代谢组学分析。结果Mdr 1a/1b/Bcrp（-/-）小鼠皮炎模型的瘙痒和抓挠行为较野生型小鼠严重，提示这些转运蛋白具有保护作用。代谢组学分析表明，Mdr 1a/1b/Bcrp（-/-）小鼠皮炎皮肤中组胺和其他皮炎相关代谢物（如尿酸盐和5-羟色胺）的浓度高于野生型小鼠，而正常皮肤中的组胺和其他皮炎相关代谢物的浓度则高于野生型小鼠。P-糖蛋白和BCRP的基因表达在恶唑酮治疗的皮肤和特应性皮炎或银屑病患者的皮肤中减少。结论这些结果提示这些外排转运蛋白可能与皮肤炎症介质相关，并且这种相关性可以在皮炎皮肤中观察到。
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.