RT Journal Article
SR Electronic
T1 Interindividual regulation of the BCRP/ABCG2 transporter in term human placentas
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.117.079228
DO 10.1124/dmd.117.079228
A1 Kristin M Bircsak
A1 Jamie E Moscovitz
A1 Xia Wen
A1 Faith Archer
A1 Poi Yu Sofia Yuen
A1 Moiz Mohammed
A1 Naureen Memon
A1 Barry I Weinberger
A1 Laura M Saba
A1 Anna M Vetrano
A1 Lauren M Aleksunes
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/01/31/dmd.117.079228.abstract
AB The breast cancer resistance protein (BCRP/ABCG2) is a maternally-facing efflux transporter that regulates the placental disposition of chemicals. Transcription factors and gene variants are important regulatory factors that influence transporter expression. Here, we sought to identify the genetic and transcriptional mechanisms underlying the interindividual expression of BCRP mRNA and protein across 137 term placentas from uncomplicated pregnancies. Placental expression of BCRP and regulatory transcription factor mRNAs was measured using multiplex branched DNA analysis. BCRP expression and ABCG2 genotypes were determined using western blot and Fluidigm Biomark genetic analysis, respectively. Placentas were obtained from a racially and ethnically diverse population including Caucasian (33%), African American (14%), Asian (14%), Hispanic (15%) and mixed (16%) backgrounds as well as unknown origins (7%). Between placentas, BCRP mRNA and protein varied up to 47-fold and 14-fold, respectfully. In particular, BCRP mRNA correlated significantly with known transcription factor mRNAs including NRF2 and AHR. Somewhat surprisingly, single nucleotide polymorphisms (SNPs) in the ABCG2 non-coding regions were not associated with variation in placental BCRP mRNA or protein. Instead, the coding region polymorphism (C421A/Q141K) corresponded with 40-50% lower BCRP protein in 421C/A and 421A/A placentas compared to wild-types (421C/C). While BCRP protein and mRNA expression weakly correlated (r=0.25, p=0.040), this relationship was absent in individuals expressing the C421A variant allele. The results of this study contribute to our understanding of the interindividual regulation of BCRP expression in term placentas and may help to identify infants at risk for increased fetal exposure to chemicals due to low expression of this efflux protein.