scholarly journals Enantioselective Drug Recognition by Drug Transporters

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3062 ◽  
Author(s):  
Yuichi Uwai
Keyword(s):  
Drug Transporters ◽  
Organic Anion ◽  
Cancer Resistance ◽  
Multidrug Resistance Proteins ◽  
Inhibitory Effects ◽  
Organic Anion Transporting Polypeptides ◽  
Resistance Proteins ◽  
Anion Transporters ◽  
Resistance Protein ◽  
The Relationship

Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters (OCTs/SLC22), and multidrug and toxin extrusions (MATEs/SLC47) have been isolated, and their functions have been elucidated. Enantioselectivity has been demonstrated in the pharmacokinetics and efficacy of drugs, and is important for elucidating the relationship with recognition of drugs by drug transporters from a chiral aspect. Enantioselectivity in the transport of drugs by drug transporters and the inhibitory effects of drugs on drug transporters has been summarized in this review.

scholarly journals Imaging of hepatic drug transporters with [131I]6-β-iodomethyl-19-norcholesterol

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Masato Kobayashi ◽  
Kodai Nishi ◽  
Asuka Mizutani ◽  
Tsuzumi Hokama ◽  
Miki Matsue ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Human Liver ◽  
Drug Transporters ◽  
Organic Anion ◽  
Hek293 Cells ◽  
Emission Computed Tomography ◽  
Cancer Resistance ◽  
Mouse Blood ◽  
Hepatic Drug ◽  
Resistance Protein

Abstract We examined whether [131I]6-β-iodomethyl-19-norcholesterol (NP-59), a cholesterol analog, can be used to measure function of hepatic drug transporters. Hepatic uptake of NP-59 with and without rifampicin was evaluated using HEK293 cells expressing solute carrier transporters. The stability of NP-59 was evaluated using mouse blood, bile, and liver, and human liver S9. Adenosine triphosphate-binding cassette (ABC) transporters for bile excretion were examined using hepatic ABC transporter vesicles expressing multidrug resistance protein 1, multidrug resistance-associated protein (MRP)1-4, breast cancer resistance protein (BCRP), or bile salt export pump with and without MK-571 and Ko143. Single photon emission computed tomography (SPECT) was performed in normal mice injected with NP-59 in the presence or absence of Ko143. Uptake of NP-59 into HEK293 cells expressing organic anion transporting polypeptide (OATP)1B1 and OATP1B3 was significantly higher than that into mock cells and was inhibited by rifampicin. NP-59 was minimally metabolized in mouse blood, bile, and liver, and human liver S9 after 120 min of incubation. In vesicles, NP-59 was transported by MRP1 and BCRP. Excretion of NP-59 into bile via BCRP was observed in normal mice with and without Ko143 in the biological distribution and SPECT imaging. NP-59 can be used to visualize and measure the hepatic function of OATP1B1, OATP1B3, and BCRP.

scholarly journals Inhibitory Effects of Quercetin and Its Main Methyl, Sulfate, and Glucuronic Acid Conjugates on Cytochrome P450 Enzymes, and on OATP, BCRP and MRP2 Transporters

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2306
Author(s):  
Violetta Mohos ◽  
Eszter Fliszár-Nyúl ◽  
Orsolya Ungvári ◽  
Katalin Kuffa ◽  
Paul W. Needs ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Glucuronic Acid ◽  
Drug Transporters ◽  
Organic Anion ◽  
Methyl Sulfate ◽  
Cytochrome P450 Enzymes ◽  
Inhibitory Effects ◽  
Organic Anion Transporting Polypeptides ◽  
Cyp2d6 Activity ◽  
Biotransformation Enzymes

Quercetin is a flavonoid, its glycosides and aglycone are found in significant amounts in several plants and dietary supplements. Because of the high presystemic biotransformation of quercetin, mainly its conjugates appear in circulation. As has been reported in previous studies, quercetin can interact with several proteins of pharmacokinetic importance. However, the interactions of its metabolites with biotransformation enzymes and drug transporters have barely been examined. In this study, the inhibitory effects of quercetin and its most relevant methyl, sulfate, and glucuronide metabolites were tested on cytochrome P450 (CYP) (2C19, 3A4, and 2D6) enzymes as well as on organic anion-transporting polypeptides (OATPs) (OATP1A2, OATP1B1, OATP1B3, and OATP2B1) and ATP (adenosine triphosphate) Binding Cassette (ABC) (BCRP and MRP2) transporters. Quercetin and its metabolites (quercetin-3′-sulfate, quercetin-3-glucuronide, isorhamnetin, and isorhamnetin-3-glucuronide) showed weak inhibitory effects on CYP2C19 and 3A4, while they did not affect CYP2D6 activity. Some of the flavonoids caused weak inhibition of OATP1A2 and MRP2. However, most of the compounds tested proved to be strong inhibitors of OATP1B1, OATP1B3, OATP2B1, and BCRP. Our data demonstrate that not only quercetin but some of its conjugates, can also interact with CYP enzymes and drug transporters. Therefore, high intake of quercetin may interfere with the pharmacokinetics of drugs.

The short-chain fatty acid butyrate is a substrate of breast cancer resistance protein

2011 ◽  
Vol 301 (5) ◽  
pp. C984-C994 ◽  
Author(s):  
Pedro Gonçalves ◽  
Inês Gregório ◽  
Fátima Martel
Keyword(s):  
Breast Cancer ◽  
Folic Acid ◽  
Breast Cancer Resistance Protein ◽  
Human Colon ◽  
Cancer Resistance ◽  
Multidrug Resistance Proteins ◽  
Resistance Proteins ◽  
Sulforhodamine B ◽  
Proliferation And Differentiation ◽  
Resistance Protein

Colorectal cancer is one of the most common cancers worldwide. Butyrate (BT) plays a key role in colonic epithelium homeostasis. The aim of this work was to investigate the possibility of BT being transported by P-glycoprotein (MDR1), multidrug resistance proteins (MRPs), or breast cancer resistance protein (BCRP). Uptake and efflux of 14C-BT and 3H-folic acid were measured in Caco-2, IEC-6, and MDA-MB-231 cell lines. mRNA expression of BCRP was detected by RT-PCR. Cell viability, proliferation, and differentiation were quantified with the lactate dehydrogenase, sulforhodamine B, and alkaline phosphatase activity assays, respectively. In both IEC-6 cells and Caco-2 cells, no evidence was found for the involvement of either MDR1 or MRPs in 14C-BT efflux from the cells. In contrast, several lines of evidence support the conclusion that BT is a substrate of both rat and human BCRP. Indeed, BCRP inhibitors reduced 14C-BT efflux in IEC-6 cells, both BT and BCRP inhibitors significantly decreased the efflux of the known BCRP substrate 3H-folic acid in IEC-6 cells, and BCRP inhibitors reduced 14C-BT efflux in the BCRP-expressing MDA-MB-231 cell line. In IEC-6 cells, combination of BT with a BCRP inhibitor significantly potentiated the effect of BT on cell proliferation. The results of this study, showing for the first time that BT is a BCRP substrate, are very important in the context of the high levels of BCRP expression in the human colon and the anticarcinogenic and anti-inflammatory role of BT at that level. So, interaction of BT with BCRP and with other BCRP substrates/inhibitors is clearly of major importance.

scholarly journals Protein Abundance of Clinically Relevant Drug Transporters in The Human Kidneys

2019 ◽  
Vol 20 (21) ◽  
pp. 5303 ◽  
Author(s):  
Stefan Oswald ◽  
Janett Müller ◽  
Ute Neugebauer ◽  
Rita Schröter ◽  
Edwin Herrmann ◽  
...  
Keyword(s):  
Drug Transporters ◽  
Organic Anion ◽  
Tubular Secretion ◽  
Transport Processes ◽  
Protein Abundance ◽  
Multidrug Resistance Proteins ◽  
Anion Transporters ◽  
Slc Transporters ◽  
Potential Factors ◽  
The Impact

Renal drug transporters such as the organic cation transporters (OCTs), organic anion transporters (OATs) and multidrug resistance proteins (MRPs) play an important role in the tubular secretion of many drugs influencing their efficacy and safety. However, only little is known about the distinct protein abundance of these transporters in human kidneys, and about the impact of age and gender as potential factors of inter-subject variability in their expression and function. The aim of this study was to determine the protein abundance of MDR1, MRP1-4, BCRP, OAT1-3, OCT2-3, MATE1, PEPT1/2, and ORCTL2 by liquid chromatography-tandem mass spectrometry-based targeted proteomics in a set of 36 human cortex kidney samples (20 males, 16 females; median age 53 and 55 years, respectively). OAT1 and 3, OCT2 and ORCTL2 were found to be most abundant renal SLC transporters while MDR1, MRP1 and MRP4 were the dominating ABC transporters. Only the expression levels of MDR1 and ORCTL2 were significantly higher abundant in older donors. Moreover, we found several significant correlations between different transporters, which may indicate their functional interplay in renal vectorial transport processes. Our data may contribute to a better understanding of the molecular processes determining renal excretion of drugs.

scholarly journals Subcellular Localization and Activity of Multidrug Resistance Proteins

2003 ◽  
Vol 14 (8) ◽  
pp. 3389-3399 ◽  
Author(s):  
Asha Rajagopal ◽  
Sanford M. Simon
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Intracellular Localization ◽  
Cancer Resistance ◽  
Multidrug Resistance Proteins ◽  
Cellular Accumulation ◽  
Cellular Targets ◽  
Resistance Proteins ◽  
Transporter Family ◽  
Resistance Protein

The multidrug resistance (MDR) phenotype is associated with the overexpression of members of the ATP-binding cassette family of proteins. These MDR transporters are expressed at the plasma membrane, where they are thought to reduce the cellular accumulation of toxins over time. Our data demonstrate that members of this family are also expressed in subcellular compartments where they actively sequester drugs away from their cellular targets. The multidrug resistance protein 1 (MRP1), P-glycoprotein, and the breast cancer resistance protein are each present in a perinuclear region positive for lysosomal markers. Fluorescence-activated cell sorting analysis suggests that these three drug transporters do little to reduce the cellular accumulation of the anthracycline doxorubicin. However, whereas doxorubicin enters cells expressing MDR transporters, this drug is sequestered away from the nucleus, its subcellular target, in vesicles expressing each of the three drug resistance proteins. Using a cell-impermeable inhibitor of MRP1 activity, we demonstrate that MRP1 activity on intracellular vesicles is sufficient to confer a drug resistance phenotype, whereas disruption of lysosomal pH is not. Intracellular localization and activity for MRP1 and other members of the MDR transporter family may suggest different strategies for chemotherapeutic regimens in a clinical setting.

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