Characterization and analyses of multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in Chinese population

Ji Ye Yin, Qiong Huang, Youyun Yang, Jian Ting Zhang, Mei Zuo Zhong, Hong Hao Zhou, Zhao Qian Liu

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Objective To explore the distribution frequencies of four common single nucleotide polymorphisms (SNPs) of MRP1/ABCC1 in a mainland Chinese population and investigate whether these SNPs affect the expression and function of the MRP1/ABCC1. Methods The genotype of 208 healthy volunteers was determined using PCR-restriction fragment length polymorphism. The four candidated SNPs were recreated by site-directed mutagenesis and tested for their effect on MRP1/ABCC1 expression and multidrug resistance function in stable transfected HEK293 and CHO-K1 cell lines. Real-time PCR, western blot and confocal microscopy were used to determine the mRNA, protein expression, and protein trafficking. At last, the effect of mutations on MRP1/ABCC1-mediate drug resistance was determined using methyl thiazolyl tetrazolium assay. Results The allelic frequencies of Cys43Ser (128G>C), Thr73IIe (218C>T), Arg723GIn (2168G>A), and Arg1058GIn (3173G>A) in mainland Chinese were 0.5, 1.4, 5.8, and 0.5%, respectively. None of these mutations had any effect on MRP1/ABCC1 expression and trafficking, but that Arg723GIn mutation significantly reduced MRP1/ ABCC1-mediated resistance to daunorubicin, doxorubicin, etoposide, vinblastine, and vincristine. The Cys43Ser mutation did not affect all tested drug resistance. In contrast, the Thr73IIe mutation reduced resistance to methotrexate and etoposide, whereas the Arg1058GIn mutation increased the response of two anthracycline drugs and etoposide in HEK293 and CHO-K1 cells as well as vinblastine and methotrexate in CHO-K1 cells. Conclusion The allelic frequency of the Arg723GIn mutation is relatively higher than other SNPs in mainland Chinese population and therefore this mutation significantly reduces MRP1/ABCC1 activity in multidrug resistance.

Original languageEnglish (US)
Pages (from-to)206-216
Number of pages11
JournalPharmacogenetics and Genomics
Volume19
Issue number3
DOIs
StatePublished - Mar 2009

Keywords

  • Atp-binding cassette transporter
  • Drug resistance
  • Genetic polymorphism
  • Multidrug resistance
  • Multidrug resistance-associated protein 1 (MRP1/ABCC1)

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

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