Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON M5S3M2, Canada.
Drug Metab Dispos. 2010 May;38(5):740-4. doi: 10.1124/dmd.109.030791. Epub 2010 Feb 16.
The antidiabetic agent glyburide (glibenclamide) is frequently used for the treatment of type II diabetes and is increasingly being used for the treatment of gestational diabetes. Evidence suggests that breast cancer resistance protein/ATP-binding cassette, subfamily G, member 2 (ABCG2) expressed in the placenta protects the fetus against the accumulation of glyburide. A number of studies have investigated the significance of several single-nucleotide polymorphisms (SNPs) in the ABCG2 gene. Associations between the Q141K (C421A) SNP and ABCG2 protein expression, membrane surface translocation, efflux activity, or ATPase activity have been shown. Therefore, alterations in glyburide transport across the placenta, resulting in increased fetal glyburide exposure, may be seen in individuals carrying the C421A allele. The purpose of this study is to investigate whether the Q141K SNP causes alterations in ABCG2-mediated glyburide transport. Glyburide accumulation assays were carried out with stably transfected human embryonic kidney (HEK)-293 cells expressing wild-type ABCG2 (Arg482) and polymorphic ABCG2 (Q141K). Glyburide kinetic parameters were determined for comparison of wild-type and SNP ABCG2 activity by simultaneously fitting data for ABCG2-expressing cells (saturable transport) and empty vector-expressing cells (nonsaturable transport) by nonlinear regression analysis. The apparent K(t) and V(max) values for the transfected HEK-293 cells expressing the polymorphic variant (Q141K) of ABCG2 were significantly higher than those values determined for the wild-type ABCG2-expressing cells (p < 0.05). Our results indicate that the Q141K variant of ABCG2 may have the potential to alter the placental pharmacokinetics of glyburide used in pregnancy.
抗糖尿病药物格列本脲（glibenclamide）常用于治疗 2 型糖尿病，并且越来越多地用于治疗妊娠糖尿病。有证据表明，胎盘表达的乳腺癌耐药蛋白/ATP 结合盒，亚家族 G，成员 2（ABCG2）可保护胎儿免受格列本脲的积累。许多研究已经研究了 ABCG2 基因中几个单核苷酸多态性（SNP）的意义。已经显示出 Q141K（C421A）SNP 与 ABCG2 蛋白表达，膜表面转位，外排活性或 ATP 酶活性之间的关联。因此，在携带 C421A 等位基因的个体中，可能会看到格列本脲穿过胎盘的转运发生改变，导致胎儿格列本脲暴露增加。本研究的目的是研究 Q141K SNP 是否导致 ABCG2 介导的格列本脲转运改变。用稳定转染表达野生型 ABCG2（Arg482）和多态性 ABCG2（Q141K）的人胚肾（HEK）-293 细胞进行格列本脲积累测定。通过非线性回归分析同时拟合表达 ABCG2 的细胞（饱和转运）和空载体表达细胞（非饱和转运）的数据，比较野生型和 SNP ABCG2 活性以确定格列本脲动力学参数。表达多态性变体（Q141K）的 ABCG2 的转染 HEK-293 细胞的表观 K（t）和 V（max）值明显高于野生型 ABCG2 表达细胞确定的值（p <0.05）。我们的结果表明，ABCG2 的 Q141K 变体可能有改变妊娠期间使用的格列本脲胎盘药代动力学的潜力。
