Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1)
Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1)
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DOI：
10.1097/00008571-200405000-00006
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发表时间：
2004-05-01
期刊：
影响因子：
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通讯作者：
Schwab, M
中科院分区：
文献类型：
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作者：
Hitzl, M;Schaeffeler, E;Schwab, M
人胎盘中的MDR1基因产物p -糖蛋白对保护胎儿免受意外的有害药物暴露很重要，但也对限制母亲服药后治疗药物进入胎儿很重要。MDR1基因外显子26 （C3435T）的多态性先前已被证明与小肠、肾脏和淋巴细胞中p -糖蛋白表达减少有关。在本研究中，我们系统地研究了MDR1多态性是否也影响人胎盘中p -糖蛋白的表达。本文分析了73例高加索人足月胎盘中MDR1 mRNA和p -糖蛋白的表达，以及MDR1基因型/单倍型对母婴C3435T和G2677T/A多态性的影响。mdr1m RNA水平在这些基因型组之间没有差异。然而，当母亲和婴儿均为3435T等位基因纯合子（TT/ TT）时，P-糖蛋白的表达显著低于母亲和胎儿的c等位基因纯合子（TT/ TT为0.40 +/- 0.18 a.u.， CC/ CC为0.66 +/- 0.30 a.u., P = 0.01）。此外，携带两种多态性（3435T和2677T； TT/TT）的母亲胎盘的P-糖蛋白表达量（0.31 +/- 0.12 a.u.）也显著低于野生型个体的胎盘（CC/GG, 0.71±0.31 a.u., P = 0.02）。综上所述，MDR1多态性C3435T和G2677T与人类胎盘中p -糖蛋白表达的改变有关，并且可能由于胎儿基因决定的、可变的药物暴露而产生临床后果。(C) 2004利平科特·威廉姆斯·威尔金斯。
The MDR1 gene product P-glycoprotein in the human placenta is important for protecting the fetus from unintended, harmful drug exposure, but also for limiting the access of therapeutic drugs to the fetus after maternal drug intake. A polymorphism in exon 26 of the MDR1 gene (C3435T) has previously been shown to be associated with reduced P-glycoprotein expression in the small intestine, kidney and lymphocytes. In the present study, we examined systematically whether MDR1 polymorphisms also have an impact on P-glycoprotein expression in the human placenta. MDR1 mRNA and P-glycoprotein were analysed in 73 full-term human placentas of Caucasians, as well as respective MDR1 genotypes/haplotypes, for the C3435T and G2677T/A polymorphisms of mothers and infants. MDR1 m RNA levels were not different between these genotype groups. However, P-glycoprotein expression was significantly lower when both mother and infant were homozygous for the 3435T allele (TT/tt) compared to maternal and fetal homozygotes for the C-allele (0.40 +/- 0.18 a.u. for TT/tt versus 0.66 +/- 0.30 a.u. for CC/cc, P = 0.01). Moreover, placentas from mothers carrying both polymorphisms (3435T and 2677T; TT/TT) also had a significantly lower P-glycoprotein expression (0.31 +/- 0.12 a.u.) compared to placentas of wild-type individuals (CC/GG, 0.71 +/- 0.31 a.u., P = 0.02). Taken together, the MDR1 polymorphisms C3435T and G2677T are associated with altered P-glycoprotein expression in the human placenta, and may have clinical consequences due to genetically determined, variable drug exposure of the fetus. (C) 2004 Lippincott Williams Wilkins.