title: The adenosine transporter, ENT1, in cardiomyocytes is sensitive to inhibition by ethanol in a kinase-dependent manner: implications for ethanol-dependent cardioprotection and nucleoside analog drug cytotoxicity.
abstract: The adenosine transporter 1 (ENT1) transports nucleosides, such as adenosine, and cytotoxic nucleoside analog drugs. ENT1 is well established to play a role in adenosinergic signaling in the cardiovascular system by modulating adenosine levels. Moderate ethanol consumption is cardioprotective and underlying mechanisms of action are not clear although adenosinergic signaling has been implicated. Here, we show that ethanol (5-200 mM) significantly reduces ENT1-dependent [(3)H] 2-chloroadenosine uptake (by up to 27 %) in the cardiomyocyte cell line, HL-1. Inhibition or absence of ENT1 is known to be cardioprotective, suggesting that the interaction of ethanol with ENT1 may promote adenosinergic cardioprotective pathways in the cardiovasculature.Ethanol sensitivity of adenosine uptake is altered by pharmacological activation of PKA and PKC. Primary cardiomyocytes from PKCε-null mice have significantly greater sensitivity to inhibition (by approximately 37 %) of adenosine uptake by ethanol than controls. These data suggest that the presence of ethanol may compromise ENT1-dependent nucleoside analog drug cytotoxicity, and indeed, ethanol (5 mM) reduces the cytotoxic effects of gemcitabine (2 nM), an anti-cancer drug, in the human cancer cell line, HTB2. Thus, the pharmacological inhibition of ENT1 by ethanol may contribute to ethanol-dependent cardioprotection but compromise gemcitabine cytotoxicity.
authors.affiliation: Muscle Health Research Centre, York University, Toronto, Canada.
authors.forename: Azza
authors.initials: A
authors.lastname: Ramadan
authors.forename: Zlatina
authors.initials: Z
authors.lastname: Naydenova
authors.forename: Katarina
authors.initials: K
authors.lastname: Stevanovic
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Rose
authors.forename: Imogen R
authors.initials: IR
authors.lastname: Coe
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000633:toxicity; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D002492:Central Nervous System Depressants; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; C498476:SLC29A1 protein, mouse; D003841:Deoxycytidine; D000431:Ethanol; D051744:Protein Kinase C-epsilon; D000241:Adenosine; D000093542:Gemcitabine