Oxidative bioactivation and toxicity of leflunomide in immortalized human hepatocytes and kinetics of the non-enzymatic conversion to its major metabolite, A77 1726.

We used immortalized human hepatocytes to study the bioactivation of leflunomide and the metabolic degradation to its major metabolite, A77 1726. Both leflunomide and A77 1726 caused a time- and concentration-dependent increase in LDH release. The cytotoxicity of leflunomide, but not that of A77 1726, was prevented by the pan-CYP inhibitor, 1-aminobenzotriazole, indicating that an oxidative metabolite(s) was responsible for the cell injury.

Leflunomide or A77 1726 protect from acetaminophen-induced cell injury through inhibition of JNK-mediated mitochondrial permeability transition in immortalized human hepatocytes.

Leflunomide, a disease-modifying anti-rheumatic drug, protects against T-cell-mediated liver injury by poorly understood mechanisms. The active metabolite of leflunomide, A77 1726 (teriflunomide) has been shown to inhibit stress-activated protein kinases (JNK pathway), which are key regulators of mitochondria-mediated cell death. Therefore, we hypothesized that leflunomide may protect from drugs that induce the mitochondrial permeability transition (mPT) by blocking the JNK signaling pathway.