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.
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 cancerpatients 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.
Authors: R Arlanov; T Lang; G Jedlitschky; E Schaeffeler; T Ishikawa; M Schwab; A T Nies Journal: Pharmacogenomics J Date: 2015-04-21 Impact factor: 3.550
Authors: S Hamzic; N Wenger; T K Froehlich; M Joerger; S Aebi; C R Largiadèr; U Amstutz Journal: Pharmacogenomics J Date: 2016-03-22 Impact factor: 3.550