The β-amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor JNJ-54861911, a candidate for the treatment of Alzheimer's disease, was withdrawn from clinical trials due to drug-induced liver inj Show more
The β-amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor JNJ-54861911, a candidate for the treatment of Alzheimer's disease, was withdrawn from clinical trials due to drug-induced liver injury (DILI). This paper describes our investigation of the metabolism of JNJ-54861911 to understand the potential contribution to the observed DILI. In human hepatocytes, JNJ-54861911 is metabolized by CYP450 3A4 to a reactive intermediate (RI), which undergoes glutathione (GSH) addition at C6 of the 2-amino-4-methyl-1,3-thiazin-4-yl moiety via glutathione S-transferase α1 (GSTA1) catalysis. Despite the preponderant role of CYP3A4 as an enabler, the adduct has the same level of oxidation as that of JNJ-54861911. The exact mechanism of RI formation might involve a sulfoxide (with further reduction) or tautomeric forms of JNJ-54861911 bearing a reactive thiazinium cation activating both the C2 and C6 positions. The cell pellet from the human hepatocyte incubated with Show less
Human cohort studies have demonstrated a role for systemic metabolic dysfunction in osteoarthritis (OA) pathogenesis in obese patients. To explore the mechanisms underlying this metabolic phenotype of Show more
Human cohort studies have demonstrated a role for systemic metabolic dysfunction in osteoarthritis (OA) pathogenesis in obese patients. To explore the mechanisms underlying this metabolic phenotype of OA, we examined cartilage degradation in the knees of mice from different genetic backgrounds in which a metabolic phenotype was established by various dietary approaches. Wild-type C57BL/6J mice and genetically modified mice (hCRP, LDLr Metabolic phenotypes were confirmed in all studies as mice developed obesity, hypercholesteremia, glucose intolerance and/or insulin resistance. Aggravated cartilage degradation was only observed in two out of the twelve experimental setups, specifically in long-term studies in male hCRP and female ApoE*3Leiden.CETP mice. C57BL/6J and LDLr Long-term feeding of high-caloric diets consistently induced a metabolic phenotype in various C57BL/6J (-based) mouse strains. In contrast, the induction of articular cartilage degradation proved variable, which suggests that an additional trigger might be necessary to accelerate diet-induced OA progression. Gender and genetic modifications that result in a humanized pro-inflammatory state (human CRP) or lipoprotein metabolism (human-E3L.CETP) were identified as important contributing factors. Show less