ジクロフェナクは、ミトコンドリア機能障害を介して肝臓への脂質蓄積を増悪させる

抄録

[Background and Purpose] Diclofenac, a major NSAID, has hepatotoxicity and rarely induces Reye’s syndrome, which is characterized by increase in serum ALT and small lipid droplets in liver. In 1990’s, mitochondrial permeability transition (MPT), a type of mitochondrial injury, was proposed as an inducible factor in Reye’s syndrome. However, there is no report that MPT is involved in drug-induced Reye’s syndrome. Therefore, we aimed to clarify the relationship between MPT and Reye’s syndrome and liver injury induced by diclofenac using cyclophilin D knockout mice, which is deficient in MPT.

[Method] (1) Fasted female mice (C57B6/J) were treated with sublethal dose of diclofenac. After 6 h, liver injury and lipid accumulation were assessed. (2) Female mice hepatocytes were incubated with oleate and diclofenac. After 24 h, lipid accumulation was assessed.

[Results and Discussion] (1) Diclofenac increased serum ALT level after 6 h. Although tissue injury was not observed, triglyceride content in liver was higher in diclofenac-treated group than control group. Moreover, this increase was suppressed in cyclophilin D knockout mice. (2) Hepatocytes incubated with oleate and diclofenac in non-toxic dose showed lipid accumulation and it was suppressed in cyclophilin D knockout mice. Altogether, it was indicated that diclofenac exacerbated lipid accumulation in MPT-dependent manner.

[Conclusion] Our results suggest that MPT is involved in drug-induced lipid accumulation in liver, perhaps by impairing beta-oxidation.