title: Statins alter the hepatobiliary transport of unconjugated and conjugated bilirubin in sandwich-cultured rat hepatocytes.
abstract: Several studies have reported that statins occasionally cause impairment of liver functions characterized by elevated serum bilirubin levels, which might be due to altered function of the multidrug resistance-associated proteins (Mrp2/3). We aimed to study the modulation of the hepatobiliary transport of bilirubin by four statin derivatives, atorvastatin, fluvastatin, pravastatin, and rosuvastatin in sandwich-cultured rat hepatocytes. All statins except pravastatin significantly inhibited the uptake of bilirubin. The biliary efflux of bilirubin conjugates was increased by pravastatin and rosuvastatin concentration dependently. Rosuvastatin stimulated not only the Mrp2 mediated biliary, but the Mrp3 mediated sinusoidal elimination, resulting in decreased intracellular bilirubin accumulation. The significantly induced Mrp2/3 protein levels (ranging from 1.5 to 1.8-fold) accounted for the elevated efflux. Cell polarization, the formation of biliary network was also significantly increased by fluvastatin, pravastatin and rosuvastatin (151%, 216% and 275% of the control, respectively). The simultaneous inhibition of the uptake and the stimulation of the sinusoidal and canalicular elimination may explain, at least in part, the clinical observation of elevated serum bilirubin levels. In conclusion, our results suggest that in spite of the elevated serum bilirubin levels, the altered Mrp2 and Mrp3 functions by statins is probably not associated with hepatotoxic effects.
authors.affiliation: Institute of Molecular Pharmacology, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar Tudósok körútja 2, Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Szabó
authors.affiliation: Institute of Molecular Pharmacology, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar Tudósok körútja 2, Hungary.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Veres
authors.affiliation: Institute of Molecular Pharmacology, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar Tudósok körútja 2, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Bátai-Konczos
authors.affiliation: Institute of Molecular Pharmacology, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar Tudósok körútja 2, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kékesi
authors.affiliation: Solvo Biotechnology, 6726 Szeged, Közép fasor 52, Hungary.
authors.forename: Emese
authors.initials: E
authors.lastname: Kis
authors.affiliation: Solvo Biotechnology, 6726 Szeged, Közép fasor 52, Hungary.
authors.forename: Kitti
authors.initials: K
authors.lastname: Szabó
authors.affiliation: Institute of Molecular Pharmacology, Research Centre for Natural Sciences, HAS, 1117 Budapest, Magyar Tudósok körútja 2, Hungary. Electronic address: jemnitz.katalin@ttk.mta.hu.
authors.forename: Katalin
authors.initials: K
authors.lastname: Jemnitz
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin; D001663:Bilirubin / Q000378:metabolism*; D001692:Biological Transport; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D000077340:Fluvastatin; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000069059:Atorvastatin; D001663:Bilirubin; D005229:Fatty Acids, Monounsaturated; D005464:Fluorobenzenes; D000077340:Fluvastatin; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D017035:Pravastatin; D011743:Pyrimidines; D011758:Pyrroles; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; C423013:Abcc2 protein, rat; C503597:Slco1a4 protein, rat; C114462:multidrug resistance-associated protein 3
keywords: Bilirubin transport; Hepatotoxicity; Sandwich-cultured rat hepatocytes; Statin treatment