Modulation of human placental P-glycoprotein expression and activity by MDR1 gene polymorphisms

Abstract

The ABC transporter P-glycoprotein is a product of the MDR1 gene and its function in human placenta is to extrude xenobiotics from the tissue thus decreasing fetal exposure. The goal of this investigation was to examine the effect of three polymorphisms in the MDR1 gene on the expression and activity of placental P-gp. In 199 term placentas examined, the C1236T variant was associated with 11% lower P-gp protein expression than wild type, while the C3435T and G2677T/A variants each were associated with a 16% reduction (p < 0.05). Homozygotes for the C1236T and C3435T variant allele (TT) were associated with 42% and 47% increase in placental P-gp transport activity, respectively (p = 0.04 and p = 0.02) of the prototypic substrate, [ 3 H]-paclitaxel. These findings indicate that the C3435T and G2677T/A SNPs in MDR1 are significantly associated with decreased placental P-gp protein expression, while the C1236T and C3245T homozygous variants are significantly associated with an increase in its efflux activity.

Interactions of tenofovir and tenofovir disoproxil fumarate with drug efflux transporters ABCB1, ABCG2, and ABCC2; role in transport across the placenta

“…As drug-drug interactions on ABC transporters may substantially affect the fate of drugs in organism, our findings should be taken into account when TDF is co-administered with compounds whose membrane transport is mediated by ABCB1 and/ or ABCG2 such as antiretrovirals [41] or other drugs administered in pregnancy [8]. Differences in ABCB1 expression between HIV-infected and noninfected women [42] as well as genetic polymorphisms leading to altered expression and function of the protein in the placenta [43] should also be considered when substrate drugs are prescribed.…”

The Role of the Placenta in Fetal Exposure to Xenobiotics: Importance of Membrane Transporters and Human Models for Transfer Studies

“…Rahi et al (2008) reported that although SNPs altered the expression levels of P-gp in the human placenta, they did not have an effect on P-gp-mediated placental transfer of saquinavir. On the contrary, recent studies have shown that some homozygous mdr1 variants (C1236T, C3245T) are associated with an increase in placental P-gp efflux of paclitaxel (Hemauer et al, 2010). Transfected cell lines expressing the polymorphic variant (Q141K) of ABCG2 exhibit altered placental pharmacokinetics of glyburide (Pollex et al, 2010).…”

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

“…Ironically, in homozygous variants 1236T/T and 3435T/T the P-gp activity was apparently increased as shown by the transport of the prototypical P-gp substrate paclitaxel in the human term placenta compared to the homozygous wild type (C/C). The G2677T/A alleles also showed a trend toward increased P-gp activity than the homozygous wild type (C/C) (57). Further, a study by Rahi et al involving immunoblotting and genotyping by PCR in human placental samples indicated that the variant allele 3435T of P-gp caused significantly higher placental P-gp expression levels.…”