ABCC5 Gene Variant c.1146A>G Reduces MRP5 Expression and Can be a Potential Marker to Manage Cilostazol Induced Headache

Abstract

Background: Patients taking cilostazol, a representative phosphodiesterase type III inhibitor used for vasodilation, occasionally complain of headaches. Cerebral arteriolar relaxation, due to an increase in intracellular cAMP or cGMP, is believed to be associated with a severe form of cilostazol-induced headaches. Multidrug resistance protein 5 (MRP5) is an important regulator of cAMP and cGMP could be a regulatory protein of this cilostazol induced headache.Methods: The response to cilostazol on the basis of MRP5 genetic variations was studied in phase-I clinical trial including 101 healthy Korean individuals. Quantitative real time PCR, Western blot, confocal analysis and drug transporter assay was performed to detect and evaluate the activity of MRP5. Statistical analysis was performed by using SPSS 18.0 and GraphPad Prism 4.0 software. Results: Population genetic and pharmacokinetic analyses indicated that a group of MRP5 genetic variations in linkage disequilibrium with c.1146A>G (rs7636910) is associated with the no or mild forms of cilostazol-induced headaches, but did not affect the systemic distribution of cilostazol or its metabolites. Quantitative real-time PCR and pyrosequencing assays of blood cells revealed that individuals with the c.1146G allele, a protective allele against cilostazol-induced headaches, had a 0.68-fold lower mRNA expression of MRP5 than that of individuals with c.1146A allele. In addition, in a gene transfection experiment using MDCKII cells, the G variant was found to be reduced the mRNA and protein expression of MRP5.Conclusion: These results suggest that MRP5 has an important role in the regulation of cilostazol-induced chronic headache and the c.1146A>G variation could be a potential marker to manage/treat cilostazol-induced headaches.Trial registration: The trial is registered at www.clinicaltrials.gov on (October 20, 2011) and the number is NCT01455558.