Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.
Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.
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DOI：
10.1073/pnas.97.7.3473
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发表时间：
2000-03
影响因子：
11.1
通讯作者：
S. Hoffmeyer;O. Burk;O. Richter;H. Arnold;J. Brockmöller;A. Johne;I. Cascorbi;T. Gerloff;I. Root
中科院分区：
文献类型：
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作者：
S. Hoffmeyer;O. Burk;O. Richter;H. Arnold;J. Brockmöller;A. Johne;I. Cascorbi;T. Gerloff;I. Root
评价多药耐药（MDR）-1基因的改变是否与肠道MDR-1表达和口服P-糖蛋白（PGP）底物的摄取相关，我们分析了21名志愿者的MDR-1序列，这些志愿者的PGP表达和功能通过Western印迹和定量免疫组织学（n = 21）或口服地高辛后的血浆浓度测定（n = 8 + 14）。我们观察到MDR-1第26外显子（C3435 T）的多态性与MDR-1的表达水平和功能显著相关。该多态性纯合子个体的十二指肠MDR-1表达显著较低，地高辛血浆水平最高。在我们的样本人群（n = 188）的24%中观察到这种变异的纯合性。这种多态性预计会影响MDR-1的许多其他底物的吸收和组织浓度。
To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.