title: ABCC11/MRP8 polymorphisms affect 5-fluorouracil-induced severe toxicity and hepatic expression.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany.
authors.forename: Tarek
authors.initials: T
authors.lastname: Magdy
authors.forename: Rudolf
authors.initials: R
authors.lastname: Arlanov
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.forename: Thomas
authors.initials: T
authors.lastname: Lang
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klein
authors.forename: Yu
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D005472:Fluorouracil