期刊
PHARMACEUTICAL RESEARCH
卷 36, 期 7, 页码 -出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-019-2634-3
关键词
genotype; OATP1B1; phosphorylation; plasma membrane localization; polymorphism
资金
- NIH [R01 GM094268, R01GM094268-06S1]
- Presbyterian Health Foundation
- National Cancer Institute Cancer Center Support Grant [P30CA225520]
PurposeMembrane transport protein organic anion transporting polypeptide (OATP) 1B1 mediates hepatic uptake of many drugs (e.g. statins). The OATP1B1 c.521T>C (p. V174A) polymorphism has reduced transport activity. Conflicting in vitro results exist regarding whether V174A-OATP1B1 has reduced plasma membrane localization; no such data has been reported in physiologically relevant human liver tissue. Other potential changes, such as phosphorylation, of the V174A-OATP1B1 protein have not been explored. Current studies characterized the plasma membrane localization of V174A-OATP1B1 in genotyped human liver tissue and cell culture and compared the phosphorylation status of V174A- and wild-type (WT)-OATP1B1.MethodsLocalization of V174A- and WT-OATP1B1 were determined in OATP1B1 c.521T>C genotyped human liver tissue (n=79) by immunohistochemistry and in transporter-overexpressing human embryonic kidney (HEK) 293 and HeLa cells by surface biotinylation and confocal microscopy. Phosphorylation and transport of OATP1B1 was determined using P-32-orthophosphate labeling and [H-3]estradiol-17-glucuronide accumulation, respectively.ResultsAll three methods demonstrated predominant plasma membrane localization of both V174A- and WT-OATP1B1 in human liver tissue and in cell culture. Compared to WT-OATP1B1, the V174A-OATP1B1 has significantly increased phosphorylation and reduced transport.ConclusionsWe report novel findings of increased phosphorylation, but not impaired membrane localization, in association with the reduced transport function of the V174A-OATP1B1.
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