Mitochondrial dysfunction induced by leflunomide and its active metabolite

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.

Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials

“…The FDA approved the TFM in September 2012 for the treatment of adults with multiple sclerosis and it is available as a tablet for oral administration (Aubagio ® , Sanofi-Aventis). However, it has been reported that the oral administration of TFM should be performed with caution due to the high risk of severe liver injury [150]. Recent studies have demonstrated the potential of TFM as an antitumor agent in breast cancer [151], prostate cancer [152], and lung cancer [153].…”

Leflunomide attenuates oxidative stress in fetal human lung endothelial cells via superoxide dismutase 2 and catalase

“…Therefore, we investigated whether leflunomide modulates the level of a reliably measured ROS such as H 2 O 2 using HPAECs. Leflunomide in concentrations greater than 30 μM causes mitochondrial dysfunction and cytotoxicity [19, 20]. Further, drug-induced toxicity can induce oxidative stress and affect the expression of several anti-oxidant enzymes.…”

“…The biological effects of leflunomide are concentration- or dose-dependent. It exerts toxic effects, including mitochondrial dysfunction, cytotoxicity, and disrupted angiogenesis when used in high concentrations [19–21]. On the other hand, leflunomide also exerts beneficial anti-inflammatory and anti-oxidant properties in several pathological states [11, 22, 23].…”

Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review

“…Leflunomide > teriflunomide preferentially inhibits mitochondrial OXPHOS complex V (F1F0 ATP synthase) → ATP depletion and the collapse of mitochondrial membrane potential [131] .…”