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FUNCTIONAL ASSESSMENT OF ABCG2 (BCRP) GENE POLYMORPHISMS TO PROTEIN EXPRESSION IN HUMAN PLACENTA

Department of Clinical Pharmacology (D.K., K.M.) and Department of Clinical Pharmacokinetics (T.H.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Department of Hospital Pharmacy (I.I., H.T., K.O.) and Department of Obstetrics and Gynecology (J.K., N.T.), Faculty of Medicine, Division of Functional Genomics, Research Center for Bioscience and Technology (S.M., E.N.), and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences (M.O.), Tottori University, Yonago, Japan; and Graduate School of Pharmaceutical Sciences, Tokyo University (H.S., Y.S.), Tokyo, Japan

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 < 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.

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