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

Gernot Zollner1, Andrea Thueringer, Carolin Lackner

  • 1Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Digestion
|September 9, 2014
PubMed
Abstract

Insights

In cholestatic drug-induced liver injury (DILI), expression of key transporters like BSEP, MDR3, and MRP2 is often reduced. Drug-induced hepatitis causes cell loss, not transporter repression.

Area of Science:

  • Hepatology
  • Toxicology
  • Molecular Biology

Background:

  • Drug-induced liver injury (DILI) is a significant clinical challenge with unclear pathogenesis.
  • Polymorphisms in hepatobiliary transport systems are linked to DILI, suggesting a role for these proteins.

Purpose of the Study:

  • To investigate the expression and tissue distribution of hepatobiliary transport systems in patients with DILI.
  • To differentiate the impact of cholestatic versus necroinflammatory DILI on transporter expression.

Main Methods:

  • Immunohistochemical assessment of canalicular transporters: bile salt export pump (BSEP), phospholipid flippase (MDR3), and bilirubin export pump (MRP2).
  • Liver biopsies from 23 DILI patients were analyzed.

Main Results:

  • In 8 of 12 patients with cholestatic DILI (often antibiotic-induced), reduced expression of MRP2, MDR3, and BSEP was observed.
  • In contrast, 11 patients with necroinflammatory DILI (often NSAID-induced) showed normal transporter expression in preserved hepatocytes, with overall reduction due to cell loss.

Conclusions:

  • Canalicular ABC transporter expression is significantly altered in most cases of cholestatic DILI.
  • Drug-induced hepatitis results in a numerical loss of hepatocytes and bile canaliculi, rather than direct repression of transporter expression.

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