Efflux transport of nicotine, cotinine and trans-3'-hydroxycotinine glucuronides by human hepatic transporters
Autor: | Erkka Järvinen, Noora Sjöstedt, Moshe Finel, Jan B. Koenderink, Heidi Kidron |
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Přispěvatelé: | Pharmaceutical Design and Discovery group, Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Division of Pharmaceutical Biosciences, Drug Delivery Unit, Moshe Finel / Principal Investigator |
Rok vydání: | 2019 |
Předmět: |
Nicotine
ATP Binding Cassette Transporter Subfamily B lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ABCC3 METABOLISM Pharmacology Toxicology 030226 pharmacology & pharmacy MULTIDRUG-RESISTANCE PROTEINS 03 medical and health sciences chemistry.chemical_compound Glucuronides 0302 clinical medicine Multidrug Resistance Protein 1 medicine ATP Binding Cassette Transporter Subfamily G Member 2 Humans ASSAY Cotinine DISPOSITION efflux transporters Multidrug resistance-associated protein 2 Alkaloid MRP3 Biological Transport Transporter General Medicine UGT2B17 MEMBRANE TRANSPORTER Multidrug Resistance-Associated Protein 2 Neoplasm Proteins 3. Good health DRUG DISCOVERY Liver chemistry 317 Pharmacy Hepatocytes ATP-Binding Cassette Transporters Efflux Multidrug Resistance-Associated Proteins Glucuronide 030217 neurology & neurosurgery medicine.drug |
Zdroj: | Basic & Clinical Pharmacology & Toxicology, 125, 6, pp. 490-498 Basic & Clinical Pharmacology & Toxicology, 125, 490-498 |
ISSN: | 1742-7835 |
Popis: | Contains fulltext : 215788.pdf (Publisher’s version ) (Closed access) Nicotine is the addiction causing alkaloid in tobacco, and it is used in smoking cessation therapies. Although the metabolic pathways of nicotine are well known and mainly occur in the liver, the transport of nicotine and its metabolites is poorly characterized. The highly hydrophilic nature and urinary excretion of nicotine glucuronide metabolites indicate that hepatic basolateral efflux transporters mediate their excretion. We aimed here to find the transporters responsible for the hepatic excretion of nicotine, cotinine and trans-3'-hydroxycotinine (OH-cotinine) glucuronides. To this end, we tested their transport by multidrug resistance-associated proteins 1 (MRP1, ABCC1) and MRP3-6 (ABCC3-6), which are located on the basolateral membranes of hepatocytes, as well as MRP2 (ABCC2), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance protein 1 (MDR1, P-gp, ABCB1) that are expressed in the apical membranes of these cells. ATP-dependent transport of these glucuronides was evaluated in inside-out membrane vesicles expressing the transporter of interest. In addition, potential interactions of both the glucuronides and parent compounds with selected transporters were tested by inhibition assays. Considerable ATP-dependent transport was observed only for OH-cotinine glucuronide by MRP3. The kinetics of this transport activity was characterized, resulting in an estimated Km value of 895 micromol/L. No significant transport was found for nicotine or cotinine glucuronides by any of the tested transporters at either 5 or 50 micromol/L substrate concentration. Furthermore, neither nicotine, cotinine nor OH-cotinine inhibited MRP2-4, BCRP or MDR1. In this study, we directly examined, for the first time, efflux transport of the three hydrophilic nicotine glucuronide metabolites by the major human hepatic efflux transporters. Despite multiple transporters studied here, our results indicate that an unknown transporter may be responsible for the hepatic excretion of nicotine and cotinine glucuronides. |
Databáze: | OpenAIRE |
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