Toxicology. 2018 Feb 7. pii: S0300-483X(18)30017-9. doi: 10.1016/j.tox.2018.02.003. [Epub ahead of print]
Mitochondrial dysfunction induced by leflunomide and its active metabolite.
Xuan J, Ren Z, Qing T, Couch L, Shi L, Tolleson WH, Guo L.
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.
When you balance the risk, is the benefit worth it? All medicines have side effects. Laughter is the only medicine that I know of without side effects (or no visible signs of one)! Understanding the nature of side effects is an art form, a study named toxicology. The goal as far as I’m aware is to at least mitigate the more serious side effects by determining susceptibility.
Before teriflunomide (Aaubagio) came on the scene, there was leflunomide, which is anti-inflammatory treatment used in rheumatoid arthritis. It’s active component is teriflunomide (also known as A77 1726), so not surprisingly they have similar side effects, particularly considering that they have similar blood levels at the recommended treatment dosages. The most important side effect is the liver dysfunction. It is therefore prohibited in those with existing severe hepatic impairment and two weekly blood monitoring is a must for the first six months (see EMA summary of product characteristics for aubagio). The exact mechanism by which the liver injury occurs has always remained somewhat of a mystery.
The clue to side effects may be in the mode of action of the medicine. The mode of action of teriflunomide is thought to be via inhibition of dihydroorotate dehydrogenase, a key mitochondrial enzyme in pyrimidine synthesis. Drug-induced mitochondrial dysfunction is thought to be a major cause for liver injury in many medicines. This is not surprising since mitochondria are major source of cellular energy production.
Therefore, using liver cells in the laboratory the authors investigate whether, leflunomide and teriflunomide both cause mitochondrial toxicity.
They discovered that when liver cells were exposed to the two drugs, the production of energy (ATP) by the mitochondria started to decrease in a dose dependent manner, suggesting that this may be the mode of toxicity. There was also evidence of damage to cellular integrity (through the leakage of LDH) throughout. Leflunomide, unlike teriflunomide was demonstrated to cause a more severe liver injury, however.
Overall, in either case it would be important to avoid exacerbating a per-exisiting liver disorders by adding these drugs on top. Although mandatory, regular monitoring can lull one into a false sense of security, most side effects by nature are unpredictable.