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

Area of Science:

• Pharmacogenomics
• Cancer Therapeutics
• Drug Metabolism

Background:

• 5-fluorouracil (5-FU) is a widely used chemotherapy agent.
• 5-FdUMP, an active metabolite of 5-FU, is processed by MRP8 (ABCC11).
• Genetic variations in ABCC11 may influence 5-FU toxicity.

Purpose of the Study:

• To investigate the association between ABCC11 gene polymorphisms and severe toxicity in cancer patients treated with 5-FU.
• To determine the functional impact of identified ABCC11 polymorphisms on MRP8 protein expression and function.

Main Methods:

• Genotyping of 12 ABCC11 tag SNPs in 672 cancer patients treated with 5-FU.
• Assessment of toxicity using WHO criteria.
• Functional analysis using a Caucasian human liver cohort (n=150) and recombinant MRP8 protein expression.

Main Results:

• The rs17822471 (G>A, T546M) polymorphism in ABCC11 was identified as a risk factor for severe leukopenia (p=0.021).
• MRP8 protein expression was 1.7-fold lower in carriers of rs17822471 compared to wild-type individuals (p=0.02).
• Recombinant expression studies confirmed the impact of T546M on MRP8 protein levels.

Conclusions:

• The ABCC11 rs17822471 polymorphism is associated with an increased risk of severe leukopenia in 5-FU treated patients.
• Lower MRP8 expression in bone marrow and leukocytes may lead to 5-FdUMP accumulation, contributing to leukopenia.
• ABCC11 genotyping could aid in personalized 5-FU chemotherapy to mitigate toxicity.