Acetaminophen alters microsomal ryanodine Ca2+ channel in HepG2 cells overexpressing CYP2E1

Biochemical Pharmacology
A Holownia, J J Braszko

Abstract

Acetaminophen hepatotoxicity is mediated by an initial metabolic activation and covalent binding of drug metabolites to liver proteins. Acetaminophen metabolites have been shown to affect rat liver microsomal Ca2+ stores, but the mechanism is not well understood. The aim of the current work was to find out if the metabolism of acetaminophen by CYP2E1 affects ryanodine-sensitive Ca2+ stores in the endoplasmic reticulum of transduced HepG2 cells. Five millimoles acetaminophen decreased proliferation of CYP2E1-overexpressing HepG2 cells, increased cytosolic Ca2+ levels and produced significant cytotoxicity, while only little, mostly anti-proliferative effects were found in HepG2 cells lacking CYP2E1. CYP2E1 inhibitor-4-methylpyrazole decreased drug cytotoxicity in transduced cells and normalized elevated Ca2+ levels. Acetaminophen cytotoxicity was significantly higher in CYP2E1 expressing cells with depleted glutathione. In the cells engineered to overexpress CYP2E1, an increased [3H]ryanodine affinity (by 45%) and increased ligand maximal binding to ryanodine receptors (by 64%) was observed, most probably due to increased association rate of [3H]ryanodine. Ca2+ loading was decreased by about 53% in microsomal fractions isolated f...Continue Reading

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Citations

Aug 30, 2008·Naunyn-Schmiedeberg's Archives of Pharmacology·Adam HolowniaJan J Braszko
Jun 22, 2012·Bioinorganic Chemistry and Applications·Amir PouriaMasoud Alizadeh
Nov 1, 2005·Drug Metabolism Reviews·Alastair E CribbLaetitia Schneider
Jul 31, 2013·Journal of Pharmaceutical Sciences·Analia NovakCarolina I Ghanem
Jan 24, 2009·Pathophysiology : the Official Journal of the International Society for Pathophysiology·Ethel A WilhelmCristina W Nogueira
Dec 15, 2007·Free Radical Biology & Medicine·Yongke Lu, Arthur I Cederbaum
Jan 15, 2017·BMC Complementary and Alternative Medicine·Liliana Torres GonzálezPaula Cordero Pérez
Sep 28, 2016·Expert Opinion on Drug Metabolism & Toxicology·M José Gómez-LechónM Teresa Donato
Apr 26, 2007·Macromolecular Bioscience·Loredana De BartoloEnrico Drioli
Nov 18, 2021·Toxicology Letters·Ali Mohammad Pourbagher-ShahriOmid Mehrpour

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