Statins alter the hepatobiliary transport of unconjugated and conjugated bilirubin in sandwich-cultured rat hepatocytes

Mónika Szabó, Z. Veres, Attila Bátai-Konczos, Orsolya Kékesi, Emese Kis, Kitti Szabó, K. Jemnitz

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1136-1143
Number of pages8
JournalToxicology in Vitro
Volume28
Issue number6
DOIs
Publication statusPublished - 2014

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Bilirubin
Rats
Hepatocytes
Pravastatin
fluvastatin
Serum
Multidrug Resistance-Associated Proteins
Liver
Observation
Modulation
Polarization
Derivatives
Rosuvastatin Calcium

Keywords

  • Bilirubin transport
  • Hepatotoxicity
  • Sandwich-cultured rat hepatocytes
  • Statin treatment

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

Statins alter the hepatobiliary transport of unconjugated and conjugated bilirubin in sandwich-cultured rat hepatocytes. / Szabó, Mónika; Veres, Z.; Bátai-Konczos, Attila; Kékesi, Orsolya; Kis, Emese; Szabó, Kitti; Jemnitz, K.

In: Toxicology in Vitro, Vol. 28, No. 6, 2014, p. 1136-1143.

Research output: Contribution to journalArticle

Szabó, Mónika ; Veres, Z. ; Bátai-Konczos, Attila ; Kékesi, Orsolya ; Kis, Emese ; Szabó, Kitti ; Jemnitz, K. / Statins alter the hepatobiliary transport of unconjugated and conjugated bilirubin in sandwich-cultured rat hepatocytes. In: Toxicology in Vitro. 2014 ; Vol. 28, No. 6. pp. 1136-1143.
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AB - 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.

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