Treatment with proteasome inhibitor bortezomib decreases organic anion transporting polypeptide (OATP) 1B3-mediated transport in a substrate-dependent manner
Publication Date
November 06, 2017
Journal
PLOS ONE
Authors
Khondoker Alam, Taleah Farasyn, Alexandra Crowe, Kai Ding, et al
Volume
12
Issue
11
Pages
e0186924
DOI
https://dx.plos.org/10.1371/journal.pone.0186924
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0186924
Scopus
85033556331
Mendeley
http://www.mendeley.com/research/treatment-proteasome-inhibitor-bortezomib-decreases-organic-anion-transporting-polypeptide-oatp-1b3m
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Mendeley | Further Information

{"title"=>"Treatment with proteasome inhibitor bortezomib decreases organic anion transporting polypeptide (OATP) 1B3-mediated transport in a substrate-dependent manner", "type"=>"journal", "authors"=>[{"first_name"=>"Khondoker", "last_name"=>"Alam", "scopus_author_id"=>"56524965200"}, {"first_name"=>"Taleah", "last_name"=>"Farasyn", "scopus_author_id"=>"56204024200"}, {"first_name"=>"Alexandra", "last_name"=>"Crowe", "scopus_author_id"=>"57194286551"}, {"first_name"=>"Kai", "last_name"=>"Ding", "scopus_author_id"=>"56087922200"}, {"first_name"=>"Wei", "last_name"=>"Yue", "scopus_author_id"=>"36464692600"}], "year"=>2017, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"29107984", "sgr"=>"85033556331", "doi"=>"10.1371/journal.pone.0186924", "scopus"=>"2-s2.0-85033556331", "pui"=>"619164638", "issn"=>"19326203"}, "id"=>"601fc0d8-c83e-31e1-a5bb-0bc9fee4a431", "abstract"=>"OATP1B1 and OATP1B3 mediate hepatic uptake of many drugs (e.g., statins) and can mediate transporter-mediated drug-drug-interactions (DDIs). Bortezomib is the first-in-class proteasome inhibitor drug approved by the U. S. Food and Drug Administration for the treatment of multiple myeloma. The potential of bortezomib to cause OATP-mediated DDIs has not been assessed. The current study investigated the involvement of the ubiquitin-proteasome system (UPS) in OATP1B1 and OATP1B3 degradation and determined the effects of proteasome inhibitors on OATP1B1- and OATP1B3-mediated transport. Co-immunoprecipitation of FLAG-OATP1B1/1B3 and HA-ubiquitin was observed in human embryonic kidney (HEK) 293 cells co-transfected with FLAG-tagged OATP1B1/OATP1B3 and hemagglutinin (HA)-tagged ubiquitin, suggesting that OATP1B1 and OATP1B3 can be ubiquitin-modified. Although blocking proteasome activity by bortezomib treatment (50 nM, 7 h) increased the endogenous ubiquitin-conjugated FLAG-OATP1B1 and FLAG-OATP1B3 in HEK293-FLAG-OATP1B1 and-OATP1B3 cells, such treatment did not affect the total protein levels of OATP1B1 and OATP1B3, suggesting that the UPS plays a minor role in degradation of OATP1B1 and OATP1B3 under current constitutive conditions. Pretreatment with bortezomib (50-250 nM, 2-7 h) significantly decreased transport of [3H]CCK-8, a specific OATP1B3 substrate, in HEK293-OATP1B3 and human sandwich-cultured hepatocytes (SCH). However, bortezomib pretreatment had negligible effects on the transport of [3H]E217βG and [3H]pitavastatin, dual substrates of OATP1B1 and OATP1B3, in HEK293-OATP1B1/1B3 cells and/or human SCH. Compared with vehicle control treatment, bortezomib pretreatment significantly decreased the maximal transport velocity (Vmax) of OATP1B3-mediated transport of CCK-8 (92.25 ± 14.2 vs. 133.95 ± 15.5 pmol/mg protein/min) without affecting the affinity constant (Km) values. Treatment with other proteasome inhibitors MG132, epoxomicin, and carfilzomib also significantly decreased OATP1B3-mediated [3H]CCK-8 transport. In summary, the current studies for the first time report ubiquitination of OATP1B1 and OATP1B3 and the apparent substrate-dependent inhibitory effect of bortezomib on OATP1B3-mediated transport. The data suggest that bortezomib has a low risk of causing OATP-mediated DDIs.", "link"=>"http://www.mendeley.com/research/treatment-proteasome-inhibitor-bortezomib-decreases-organic-anion-transporting-polypeptide-oatp-1b3m", "reader_count"=>1, "reader_count_by_academic_status"=>{"Researcher"=>1}, "reader_count_by_user_role"=>{"Researcher"=>1}, "reader_count_by_subject_area"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>0}

Scopus | Further Information

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