ABCC11/MRP8 polymorphisms affect 5-fluorouracil-induced severe toxicity and hepatic expression

Tarek Magdy, Rudolf Arlanov, Stefan Winter, Thomas Lang, Kathrin Klein, Yu Toyoda, Toshihisa Ishikawa, Matthias Schwab, Ulrich M. Zanger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Aim: Because 5-fluorodeoxyuridine monophosphate (5-FdUMP), an anabolic active metabolite of 5-fluorouracil (5-FU), is a substrate of MRP8 (encoded by ABCC11), we investigated whether ABCC11 polymorphisms play a role in severe toxicity of 5-FU. Patients & methods: Genomic DNA from 672 cancer patients treated with 5-FU monotherapy and with documented toxicity according to WHO criteria was genotyped for 12 ABCC11 tag SNPs. Functional impact of polymorphisms was assessed in a Caucasian human liver cohort (n = 150) and by recombinant expression of MRP8 protein variants. Results: Univariate and multivariate analysis identified rs17822471 (G>A, T546M) as risk factor of severe leukopenia (p = 0.021, odds ratio [95%CI]: 3.31 [1.26-8.66]) but not of other toxicity types. MRP8 protein expression in human liver was 1.7-fold lower in carriers compared with wild-type (p = 0.02). Recombinant expression confirmed the effect of T546M on protein expression. Conclusion: Since MRP8 is expressed in bone marrow blasts and leukocytes, lower expression may lead to intracellular accumulation of 5-FdUMP and increased risk of leukopenia. Original submitted 25 April 2013; Revision submitted 17 July 201.

Original languageEnglish (US)
Pages (from-to)1433-1448
Number of pages16
JournalPharmacogenomics
Volume14
Issue number12
DOIs
StatePublished - Sep 2013
Externally publishedYes

Keywords

  • 5-fluorouracil
  • ABCC11
  • drug transporter
  • drug-metabolizing enzyme
  • haplotype
  • leukopenia
  • pharmacogenetics
  • pharmacogenomics
  • polymorphism
  • toxicity

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

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