RT Journal Article
SR Electronic
T1 FUNCTIONAL ASSESSMENT OF <em>ABCG2</em> (<em>BCRP</em>) GENE POLYMORPHISMS TO PROTEIN EXPRESSION IN HUMAN PLACENTA
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 94
OP 101
DO 10.1124/dmd.104.001628
VO 33
IS 1
A1 Kobayashi, Daisuke
A1 Ieiri, Ichiro
A1 Hirota, Takeshi
A1 Takane, Hiroshi
A1 Maegawa, Shinji
A1 Kigawa, Junzo
A1 Suzuki, Hiroshi
A1 Nanba, Eiji
A1 Oshimura, Mitsuo
A1 Terakawa, Naoki
A1 Otsubo, Kenji
A1 Mine, Kazunori
A1 Sugiyama, Yuichi
YR 2005
UL http://dmd.aspetjournals.org/content/33/1/94.abstract
AB The aim of the present study was to assess the contribution of polymorphisms in the breast cancer resistance protein/ATP-binding cassette transporter G2 (BCRP/ABCG2) gene to the placental expression from a new perspective, allelic imbalance. Polymorphisms were screened by polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis followed by sequencing with DNA extracted from 100 placentas. To examine whether polymorphisms of the BCRP gene correlate with the placental BCRP expression, we determined mRNA and protein levels by quantitative real-time PCR and Western blotting, respectively. In placentas, G34A (Val12Met) and C421A (Gln141Lys) were frequently observed (18-36%), but C376T, which creates a stop codon (Gln126 stop codon), was found with an allelic frequency of 1%. The mean of the BCRP protein level was significantly lower (p &lt; 0.05) in homozygotes for the A421 allele than in those for the C421 allele, and heterozygotes had an intermediate value. To evaluate whether the C421A polymorphism acts as a cis-element in BCRP transcription, allelic imbalance was determined using informative lymphoblasts and 56 samples of placental cDNA. In most of the placental samples we tested, the difference in expression levels between the two alleles was small, and only two samples indicated a monoallelic expression (i.e., preferential expression of one allele). These results suggest that 1) the predominant allelic expression pattern of BCRP in placental samples is biallelic, and 2) the mutation C421A is not a genetic variant acting in cis, but is considered to influence the translation efficiency. The American Society for Pharmacology and Experimental Therapeutics