Leflunomide/Teriflunomide Differential Effects - Mitochondria and Hepatotoxicity

Background: Teriflunomide is a novel, once-daily, oral immunomodulator approved in the USA for the treatment of patients with relapsing multiple sclerosis. Teriflunomide is the principal active metabolite of leflunomide, which is used for the treatment of rheumatoid arthritis. The mechanism of action for both agents is selective, reversible and non-competitive inhibition of dihydro-orotate dehydrogenase (DHODH), a mitochondrial  enzyme required for de novo synthesis of pyrimidines. Teriflunomide is a 100 times more potent inhibitor of DHODH than leflunomide.  Idiosyncratic liver injury has been reported with leflunomide. Recently, multiple reports have been published establishing an important role of mitochondria in the mechanism of idiosyncratic liver toxicity.

Objectives: The objective of this work was to compare the effects of leflunomide and teriflunomide on potential mitochondrial-related mechanisms of liver toxicity.

Methods: Differences between leflunomide- and teriflunomide-induced hepatotoxicity as potentially related to mitochondrial perturbations in vitro were investigated.

Results: In isolated liver mitochondria from rats, leflunomide was found to be a 10-fold more potent inhibitor of State 3 mitochondrial respiration and a 2- to 5-fold more potent uncoupler of isolated mitochondria than teriflunomide (State 2 respiration). Mitochondria are the major source of cellular superoxide anion generation, which is used as an indicator of cellular oxidative stress. Leflunomide was found to be more potent at generating superoxide anions than teriflunomide. Lastly, leflunomide produced greater cytotoxicity in a cell line reliant on mitochondrial respiration than teriflunomide.

Conclusions: These studies indicate that leflunomide is a more potent inhibitor of mitochondrial respiration than teriflunomide. The effect of the two compounds on mitochondrial respiration is inversely proportional to their pharmacologic activities (i.e. inhibition of mitochondrial DHODH). Additional studies are needed to clarify further the role of mitochondrial toxicity on liver injury in vivo.