Multidrug resistance-associated protein 1 functions as an efflux pump of xenobiotics in the skin
Multidrug resistance-associated protein 1 functions as an efflux pump of xenobiotics in the skin
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DOI：
10.1007/s11095-005-4576-1
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发表时间：
2005-06-01
影响因子：
3.7
通讯作者：
Tsuji, A
中科院分区：
文献类型：
--
作者：
Li, Q;Kato, Y;Tsuji, A
目的.最近的研究已经确定了皮肤中几种类型的异生物质转运蛋白的基因表达。本研究的目的是研究多药耐药相关蛋白1（MRP 1）是否在皮肤中发挥作用。[C-14]格帕沙星在Mrp 1基因敲除小鼠[FVB/Mrp 1（-/-）]和正常小鼠[FVB/Mrp 1（+/+）]皮肤中的体内分布和1-[2-氨基-5-（2，7-二氯-6-羟基-3-氧代-9-氧杂蒽基）苯氧基]-2-（2-氨基-5-甲基苯氧基）乙烷-N，N，N '，N'-四乙酸（fluo 3）的转运。[C-14]格帕沙星在FVB/Mrp 1（-/-）小鼠皮肤中的组织/血浆浓度比高于FVB/Mrp 1（+/+）小鼠。在与Fluo 3五乙酰氧基甲酯孵育的无毛小鼠的皮肤切片中，在丙磺舒（2 mM）和羰基氰对三氟甲氧基苯腙（5 mM）存在下，Fluo 3的蓄积以时间依赖性方式显著增加，但在四乙基铵（2 mM）存在下未发生变化。在FVB/Mrp 1（-/-）小鼠皮肤中，Fluo 3的蓄积呈时间依赖性增加，而在FVB/Mrp 1（+/+）小鼠皮肤中未观察到增加。这些研究结果表明，Mrp 1参与[C-14]格帕沙星和Fluo 3在皮肤中的外排，可能作为屏障系统的一部分，对外源性化合物。
Purpose. Recent research has identified gene expression of several types of xenobiotic transporters in the skin. The aim of this study was to investigate whether multidrug resistance-associated protein 1 (MRP1) functions in the skin.Methods. The distribution of [C-14] grepafloxacin in vivo and the transport of 1-[2-amino-5-(2,7-dichloro-6- hydroxy-3-oxo-9-xanthenyl) phenoxy]-2-(2-amino-5-methylphenoxy) ethane-N, N, N', N'-tetraacetic acid ( fluo 3) were examined in the skin of Mrp1 knockout mice [FVB/Mrp1(-/-)] and normal mice [FVB/ Mrp1(+/+)].Results. The tissue-to-plasma concentration ratio of [C-14] grepafloxacin was higher in the skin of FVB/ Mrp1(-/-) mice than that of FVB/ Mrp1(+/+) mice. In skin slices of hairless mouse incubated with fluo 3 pentaacetoxymethyl ester, the accumulation of fluo 3 was significantly increased in the presence of probenecid ( 2 mM) and carbonyl cyanide p-trifluoromethoxyphenylhydrazone ( 5 mM) in a time-dependent manner but did not change in the presence of tetraethylammonium ( 2 mM). In FVB/ Mrp1(-/-) mouse skin, the accumulation of fluo 3 increased time-dependently, while no increase was observed in FVB/ Mrp1(+/+) mouse skin.Conclusions. These findings suggest that Mrp1 is involved in the efflux of [C-14] grepafloxacin and fluo 3 in the skin, possibly acting as part of a barrier system against xenobiotic compounds.