Dual effects of a new CYP2E1 inhibitor on gout: anti-inflammatory actions and lowered uric acid levels

Cytochrome P450 2E1 (CYP2E1) plays an important role in inflammatory disease, but the role of CYP2E1 in gout remains elusive. The pharmacokinetics in rats of Q11, a CYP2E1 inhibitor synthesized by our group, were measured. The anti-inflammatory and uric acid (UA)-lowering levels mechanism of Q11 was investigated in hyperuricemic (HUA) mice and acute gouty arthritis (AGA) rats, and in macrophage cells stimulated by monosodium urate (MSU). The half-life (t 1/2 ) of Q11 in the ankle joint and kidney was approximately 9 h, which was more than 4 times longer than that in plasma. The expression of CYP2E1 was increased in the kidneys of HUA mice and in the ankles of AGA rats. Q11 reduced plasma UA levels in HUA mice by decreasing xanthine oxidase (XOD) activity. In addition, Q11 also decreased renal inflammatory injury in HUA mice. Moreover, Q11 decreased the levels of IL-1β and TNF-α in AGA rats, increased the levels of catalase (CAT) and glutathione (GSH), and blocked the activation of the NLRP3 inflammasome. A similar phenomenon was observed in J774A.1 and THP-1 cells treated with sodium urate.CYP2E1 may be a new therapeutic target for the treatment of gout and Q11 has the dual effect of being anti-inflammatory and lowering UA. Significance Statement The specific cytochrome P450 2E1 (CYP2E1) inhibitor Q11 reduced plasma uric acid (UA) levels by decreasing xanthine oxidase (XOD) activity in a gout animal model, while attenuating joint and renal inflammatory injury through the inhibition of oxidative stress and NLRP3 inflammasome activation.