Efflux transport of nicotine, cotinine and trans-3 '-hydroxycotinine glucuronides by human hepatic transporters

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http://hdl.handle.net/10138/311406

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Jarvinen , E , Sjöstedt , N , Koenderink , J B , Kidron , H & Finel , M 2019 , ' Efflux transport of nicotine, cotinine and trans-3 '-hydroxycotinine glucuronides by human hepatic transporters ' , Basic & Clinical Pharmacology & Toxicology , vol. 125 , no. 6 , pp. 490-498 . https://doi.org/10.1111/bcpt.13281

Title: Efflux transport of nicotine, cotinine and trans-3 '-hydroxycotinine glucuronides by human hepatic transporters
Author: Jarvinen, Erkka; Sjöstedt, Noora; Koenderink, Jan B.; Kidron, Heidi; Finel, Moshe
Contributor: University of Helsinki, Pharmaceutical Design and Discovery group
University of Helsinki, Division of Pharmaceutical Biosciences
University of Helsinki, Division of Pharmaceutical Biosciences
University of Helsinki, Division of Pharmaceutical Chemistry and Technology
Date: 2019-12
Language: eng
Number of pages: 9
Belongs to series: Basic & Clinical Pharmacology & Toxicology
ISSN: 1742-7835
URI: http://hdl.handle.net/10138/311406
Abstract: 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 K-m value of 895 mu mol/L. No significant transport was found for nicotine or cotinine glucuronides by any of the tested transporters at either 5 or 50 mu mol/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.
Subject: ABCC3
efflux transporters
glucuronides
MRP3
nicotine
MULTIDRUG-RESISTANCE PROTEINS
MEMBRANE TRANSPORTER
DRUG DISCOVERY
DISPOSITION
METABOLISM
UGT2B17
ASSAY
317 Pharmacy
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