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Pharmacogenomics. 2013 Sep;14(12):1433-48. doi: 10.2217/pgs.13.139.

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

Author information

1
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany.

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.

PMID:
24024896
DOI:
10.2217/pgs.13.139
[Indexed for MEDLINE]

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