Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine

Abstract

The aim of this study was to identify the extent of genetic variability in breast cancer resistance protein (BCRP) in humans. We first analysed the sequence of BCRP cDNA from human livers and from human intestines phenotyped for expression of intestinal BCRP. We then determined the frequency of all known coding single nucleotide polymorphisms (cSNPs) using DNA from individuals representing 11 different ethnic populations. Nine SNPs including four non-synonymous and three synonymous cSNPs and two intronic SNPs were identified. Of the missense mutations, exon 2 SNP (G34A) resulted in a V12M change; exon 5 SNP (C421A) resulted in a Q141K substitution; exon 6 SNP (A616C) resulted in an I206L amino acid substitution; and exon 15 SNP (A1768T) resulted in a N590Y change in the BCRP protein. The two most frequent polymorphisms identified in the human population studied were the G34A and C421A transitions. There was marked variation in BCRP genotypes and allele frequencies in the different populations. BCRP mRNA was phenotyped in human small bowel intestinal samples by real-time polymerase chain reaction and BCRP protein was analysed on immunoblots of tissue from the same individuals. There was a 78-fold variation in expression of BCRP mRNA and significant variation in BCRP protein expression in human intestine. Expression of intestinal BCRP mRNA and protein was not different between persons expressing the common Gln141 allele compared to the Lys141 allele. Thus, common natural allelic variants of BCRP have been identified, and did not influence interindividual variation in expression of BCRP mRNA in human intestine, but remain to be tested for their effect on BCRP function.

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

“…Allelic variation as a result of SNPs results in alterations of the BCRP protein at amino acids 12 (V12M), 141 (Q141K), 206 (I206L), and 590 (N590Y), with the most frequent polymorphisms being the exon 2 SNP (G34A) and the exon 5 SNP (C421A), which produce changes in amino acids 12 and 141 (Honjo et al, 2002;Imai et al, 2002a;Zamber et al, 2003). Additionally, a splice variant was found that resulted in deletions of A315 and T316 (Imai et al, 2002a).…”

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

“…[12][13][14] BCRP also belongs to the ABC efflux transporter superfamily 26 and is widely expressed in the small intestine, liver and placenta, influencing the absorption and disposition of a variety of substrates. 27,28 It is noteworthy that Petain et al reported that IM clearance in patients carrying the ABCG2 421C/A genotype was significantly lower than in those with the 421C/C genotype.…”

Polymorphisms in ABCG2, ABCC3 and CNT1 genes and their possible impact on chemotherapy outcome of lung cancer patients

“…previously published for Caucasians by other groups. 14,23,29 For all 6 SNPs investigated, there are no significant differences in the allele frequencies when comparing SCLC with NSCLC patients.…”

“…23 A second polymorphism, ABCG2 G34A, has also been described. In cell line experiments Mizuarai et al 24 found the 34A-Allele leading to disturbed localization in the plasma membrane and decreased drug efflux, whereas Yanase et al 18 reported the drug resistance profile of the 34A variant to be similar to the wildtype.…”