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Monday, February 12th, 2018
Table of Contents

1 Introduction
5 PMID
 [F] Diseases Research  / PubMed Research Articles  /
Mitochondrial dysfunction induced by leflunomide and its active metabolite.

PubMed

 

Resource

Toxicology Feb ; ()

Authors

Xuan J1; Ren Z2; Qing T3; Couch L4; Shi L5; Tolleson WH6; Guo L7;

Author Information
  • 1Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
  • 2Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
  • 3School of Pharmacy and School of Life Sciences, Fudan University, Shanghai 200438, China.
  • 4Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
  • 5School of Pharmacy and School of Life Sciences, Fudan University, Shanghai 200438, China.
  • 6Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
  • 7School of Pharmacy and School of Life Sciences, Fudan University, Shanghai 200438, China. Electronic address: Lei.Guo@fda.hhs.gov.

Abstract

Leflunomide, an anti-inflammatory drug used for the treatment of rheumatoid arthritis, has been marked with a black box warning regarding an increased risk of liver injury. The active metabolite of leflunomide, A771726, which also carries a boxed warning about potential hepatotoxicity, has been marketed as teriflunomide for the treatment of relapsing multiple sclerosis. Thus far, however, the mechanism of liver injury associated with the two drugs has remained elusive. In this study, cytotoxicity assays showed that ATP depletion and subsequent LDH release were induced in a time- and concentration-dependent manner by leflunomide in HepG2 cells, and to a lesser extent, by A77 1726. The decline of cellular ATP levels caused by leflunomide was dramatically exacerbated when galactose was substituted for glucose as the sugar source, indicating a potential mitochondrial liability of leflunomide. By measuring the activities of immuno-captured mitochondrial oxidative phosphorylation (OXPHOS) complexes, we found that leflunomide and A77 1726 preferentially targeted complex V (F1FO ATP synthase), with IC50 values of 35.0 and 63.7 μM, respectively. Bongkrekic acid, a mitochondrial permeability transition pore blocker that targets adenine nucleotide translocase, profoundly attenuated mitochondrial membrane depolarization, ATP depletion, and LDH leakage induced by leflunomide and A77 1726. Substantial alterations of mitochondrial function at the transcript level were observed in leflunomide-treated HepG2 cells, whereas the effects of A77 1726 on the cellular transcriptome were much less profound. Our results suggest that mitochondrial dysfunction may be implicated in the hepatotoxicity associated with leflunomide and A77 1726, with the former exhibiting higher toxicity potency.

Published by Elsevier B.V.

PMID

29427785

Others

Publication Type: Journal Article


This article is licensed under the the National Library of Medicine License. It uses material from the PubMed National Library of Medicine Data.


Last Modified:   2016-03-27


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