1. Fasting potentiates diclofenac-induced liver injury via inductions of oxidative/endoplasmic reticulum stresses and apoptosis, and inhibition of autophagy by depleting hepatic glutathione in mice.
- Author
-
Kwon, Doyoung, Seo, Hyeji, Kim, Sou Hyun, Chung, Ki Wung, Lee, Jaewon, and Jung, Young-Suk
- Subjects
- *
ENDOPLASMIC reticulum , *FASTING , *LIVER injuries , *BIOTRANSFORMATION (Metabolism) , *GLUTATHIONE , *AUTOPHAGY - Abstract
Diclofenac, a widely used non-steroidal anti-inflammatory drug, can cause liver damage via its metabolic activation by hepatic CYP450s and UGT2B7. Fasting can affect drug-induced liver injury by modulating the hepatic metabolism, but its influence on diclofenac hepatotoxicity is unknown. Thus, we investigated diclofenac-induced liver damage after fasting in mice, and the cellular events were examined. Male ICR mice fasted for 16 h showed the elevation of CYP3A11, but the decreases of UGT2B7, glutathione (GSH), and GSH S-transferase-μ/-π levels in the livers. Diclofenac (200 mg/kg) injection into the mice after 16-h fasting caused more significant liver damage compared to that in the diclofenac-treated fed mice, as shown by the higher serum ALT and AST activities. Diclofenac-promoted hepatic oxidative stress (oxidized proteins, 4-hydroxynonenal, and malondialdehyde), endoplasmic reticulum (ER) stress (BiP, ATF6, and CHOP), and apoptosis (cleaved caspase-3 and cleaved PARP) were enhanced by fasting. Autophagic degradation was inhibited in the diclofenac-treated fasting mice compared to that of the corresponding fed mice. The results suggest that fasting can make the liver more susceptible to diclofenac toxicity by lowering GSH-mediated detoxification; increased oxidative/ER stresses and apoptosis and suppressed autophagic degradation may be the cellular mechanisms of the aggravated diclofenac hepatotoxicity under fasting conditions. [Display omitted] • Fasting potentiated diclofenac-induced liver injury in mice. • Fasting increased diclofenac-promoted oxidative stress, ER stress, and apoptosis. • Fasting aggravated diclofenac-induced suppression of autophagic degradation. • Fasting increased hepatic CYP3A11, but decreased GSH and GST levels. • Fasting decreased GSH-mediated diclofenac detoxification. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF