Alterations of canalicular ATP-binding cassette transporter expression in drug-induced liver injury

Digestion. 2014;90(2):81-8. doi: 10.1159/000365003. Epub 2014 Sep 4.

Abstract

Background: Drug-induced liver injury (DILI) is a major clinical problem and its pathogenesis is poorly understood. The association of DILI with polymorphisms in hepatobiliary transport systems suggests a role for transport proteins in the pathogenesis of DILI.

Aim: To investigate expression and tissue distribution of hepatobiliary transport systems in DILI.

Methods: Expression of the canalicular bile salt export pump BSEP (ABCC11), phospholipid flippase MDR3 (ABCB4) and bilirubin export pump MRP2 (ABCC2) was assessed immunohistochemically in liver biopsies from 23 patients with DILI.

Results: Of 12 patients with cholestatic DILI (mostly due to antibiotics), 8 displayed a marked reduction of MRP2, MDR3 and BSEP expression. Transporter staining was normal in 4 patients with cholestatic DILI. In 11 patients with necroinflammatory hepatocellular injury (most frequently caused by NSAIDs), transporter staining was normal in areas where hepatocyte morphology was preserved. Due to hepatocyte necrosis and the reduction of the hepatocyte number, overall transporter expression was reduced without a reduction in transporter expression at the single hepatocyte level.

Conclusions: Canalicular ABC transporter expression is profoundly disturbed in most cases of cholestatic DILI. Drug-induced hepatitis does not lead to repression of transporter expression but to hepatocyte drop-outs with a numerical loss of bile canaliculi.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters / metabolism*
  • Adult
  • Aged
  • Aged, 80 and over
  • Bile Canaliculi / metabolism*
  • Chemical and Drug Induced Liver Injury / diagnosis
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Female
  • Hepatocytes / metabolism
  • Humans
  • Male
  • Middle Aged
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / metabolism

Substances

  • ABCB11 protein, human
  • ABCC2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • multidrug resistance protein 3