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University of Helsinki

1. Tepponen, Tuomas. MDR1-transportterin inhibition tutkiminen Sf9-MDR1-vesikkeleissä.

Degree: Farmaceutiska fakulteten, 2017, University of Helsinki

Multidrug resistance protein 1 (MDR1, p-glycoprotein) belongs to the ATP-binding cassette transporter family and it's encoded by ABCB1/MDR1 gene. It is a protein which transports many different kinds of compounds out of cells, for example from endocytes to the lumen with the use of energy from ATP. MDR1 is there for a restrictive factor for several orally administered drugs. It`s important to have knowledge about MDR1-inhibitors, in order to avoid harmful drug-drug and food-drug interactions that might affect medical treatment. The purpose of this master's thesis was to optimize an in vitro MDR1-vesicle uptake method and use it to screen inhibitors from compound libraries. To optimize the method, the effect of cholesterol loading on ATP-dependent transport of test substrate N-methylquinidine (NMQ) was evaluated, transport kinetics of the vesicles and kinetics of known inhibitors were also tested. With the optimized method, screening was done with a library of 25 food additives and a library of 42 synthetic compounds. The chemical structures of the synthetic compounds were analyzed manually in order to find factors that could explain their ability to inhibit MDR1. Only one inhibitor was found among food additives: curcumin. Other additives didn't increase or decrease the ATP-dependent transport of NMQ. Several inhibitors were found from the library of synthetic compounds, also a couple of compounds were found to increase the active transport of NMQ. Results indicate, that the additives used in this study have low risk to cause MDR1 mediated interactions, if curcumin is excluded. The inhibitory effect of curcumin should be investigated in in vivo-situation, because vesicle-based in vitro-results have tendency to overestimate results. Screening results of the synthetic compounds gives more confirmation to the usefulness of the screening method. The MDR1-inhibition screening method described in this Master`s thesis is valid, and it can be used to screen different compound libraries for MDR1-inhibitors. In the future it could be used to screen different kinds of compounds, which might end up inside humans and cause interactions with drugs.

Multilääkeresistentti proteiini 1 (engl. MDR1, p-glykoproteiini, ABCB1) kuuluu ATP:a sitovien transporttereiden perheeseen ja sitä koodaa ABCB1/MDR1 geeni. Se on kuljettajaproteiini, joka toimii ATP:sta saatavalla energialla ja kuljettaa monia yhdisteitä soluista ulos, esimerkiksi endosyyteistä takaisin suolen luumeniin. MDR1 toimii siis monien suun kautta annosteltavien lääkeaineiden imeytymistä rajoittavana tekijänä. MDR1:n inhibiittoreiden tunteminen on tärkeää esimerkiksi lääke-lääke, ja ruoka-lääke interaktioiden välttämiseksi. Tämän Pro gradun tarkoituksena oli optimoida toimiva solukalvovesikkelipohjainen in vitro-menetelmä, jolla voidaan seuloa MDR1:n inhibiittoreita yhdistekirjastoista. Menetelmän optimoinnissa tutkittiin muun muassa kolesterolin vaikutusta koesubstraatti N-metyylikinidiinin (engl. n-methylquinidine, NMQ) ATP-riippuvaiseen kuljetukseen…

Subjects/Keywords: MDR1; p-glycoprotein; vesicle; transporter; N-methylquinidine; inhibitor; p-glykoproteiini; vesikkeli; transportteri; N-metyylikinidiini; inhibiittori; Biofarmaci; Biopharmacy; Biofarmasia; MDR1; p-glycoprotein; vesicle; transporter; N-methylquinidine; inhibitor; p-glykoproteiini; vesikkeli; transportteri; N-metyylikinidiini; inhibiittori

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APA (6th Edition):

Tepponen, T. (2017). MDR1-transportterin inhibition tutkiminen Sf9-MDR1-vesikkeleissä. (Masters Thesis). University of Helsinki. Retrieved from http://hdl.handle.net/10138/230252

Chicago Manual of Style (16th Edition):

Tepponen, Tuomas. “MDR1-transportterin inhibition tutkiminen Sf9-MDR1-vesikkeleissä.” 2017. Masters Thesis, University of Helsinki. Accessed August 22, 2019. http://hdl.handle.net/10138/230252.

MLA Handbook (7th Edition):

Tepponen, Tuomas. “MDR1-transportterin inhibition tutkiminen Sf9-MDR1-vesikkeleissä.” 2017. Web. 22 Aug 2019.

Vancouver:

Tepponen T. MDR1-transportterin inhibition tutkiminen Sf9-MDR1-vesikkeleissä. [Internet] [Masters thesis]. University of Helsinki; 2017. [cited 2019 Aug 22]. Available from: http://hdl.handle.net/10138/230252.

Council of Science Editors:

Tepponen T. MDR1-transportterin inhibition tutkiminen Sf9-MDR1-vesikkeleissä. [Masters Thesis]. University of Helsinki; 2017. Available from: http://hdl.handle.net/10138/230252

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