Gyógyszertranszporterek szerepe a központi idegrendszerben

Absztrakt Bár a vér–agy gát jelenlétét az emlősszervezetekben már a XX. század elején felismerték, pontos szerkezetét, illetve a benne található gyógyszertranszporter fehérjéket csak az utóbbi évtizedekben azonosították. A központi idegrendszer védelmét biztosító ATP-kötő kazettatranszporter pumpafehérjék mellett fontos szerepet játszanak az idegrendszer működésében a solute carrier transzporterek is, amelyek a táplálék- és energiaellátást biztosítják, illetve a metabolizmus során „eltakarító” funkciót is betöltenek. Az összefoglaló közlemény áttekintést ad az idegrendszerben előforduló főbb transzporter fehérjetípusokról, sejttípusonkénti lokalizációjukról, illetve a vizsgálatukra szolgáló főbb módszerekről. A közlemény második felében különböző neurodegeneratív betegségek és a patológiájukkal összefüggésbe hozható transzporter fehérjék kerülnek bemutatásra. Mindezek fényében olyan új terápiás stratégiák kerülhetnek a figyelem középpontjába, amelyek a jelenleg gyógyíthatatlan betegségek esetében jelenthetnek majd megoldást. Orv. Hetil., 2016, 157(10), 370–378

Characterization of new, efficient Mycobacterium tuberculosis topoisomerase-I inhibitors and their interaction with human ABC multidrug transporters

Drug resistant tuberculosis (TB) is a major worldwide health problem. In addition to the bacterial mechanisms, human drug transporters limiting the cellular accumulation and the pharmacological disposition of drugs also influence the efficacy of treatment. Mycobacterium tuberculosis topoisomerase-I (MtTopo-I) is a promising target for antimicrobial treatment. In our previous work we have identified several hit compounds targeting the MtTopo-I by in silico docking. Here we expand the scope of the compounds around three scaffolds associated with potent MtTopo-I inhibition. In addition to measuring the effect of newly generated compounds on MtTopo-I activity, we characterized the compounds' antimicrobial activity, toxicity in human cells, and interactions with human multidrug transporters. Some of the newly developed MtTopo-I inhibitors have strong antimicrobial activity and do not harm mammalian cells. Moreover, our studies revealed significant human ABC drug transporter interactions for several MtTopo-I compounds that may modify their ADME-Tox parameters and cellular effects. Promising new drug candidates may be selected based on these studies for further anti-TB drug development

A Unique In Vitro Assay to Investigate ABCB4 Transport Function

ABCB4 is almost exclusively expressed in the liver, where it plays an essential role in bile formation by transporting phospholipids into the bile. ABCB4 polymorphisms and deficiencies in humans are associated with a wide spectrum of hepatobiliary disorders, attesting to its crucial physiological function. Inhibition of ABCB4 by drugs may lead to cholestasis and drug-induced liver injury (DILI), although compared with other drug transporters, there are only a few identified substrates and inhibitors of ABCB4. Since ABCB4 shares up to 76% identity and 86% similarity in the amino acid sequence with ABCB1, also known to have common drug substrates and inhibitors, we aimed to develop an ABCB4 expressing Abcb1-knockout MDCKII cell line for transcellular transport assays. This in vitro system allows the screening of ABCB4-specific drug substrates and inhibitors independently of ABCB1 activity. Abcb1KO-MDCKII-ABCB4 cells constitute a reproducible, conclusive, and easy to use assay to study drug interactions with digoxin as a substrate. Screening a set of drugs with different DILI outcomes proved that this assay is applicable to test ABCB4 inhibitory potency. Our results are consistent with prior findings concerning hepatotoxicity causality and provide new insights for identifying drugs as potential ABCB4 inhibitors and substrates