Abstract
We examined the role of phospholipase D2 (PLD2) on acetaminophen (APAP)-induced acute liver injury using a PLD2 inhibitor (CAY10594). 500 mg/kg of APAP challenge caused acute liver damage. CAY10594 administration markedly blocked the acute liver injury in a dose-dependent manner, showing almost complete inhibition with 8 mg/kg of CAY10594. During the pathological progress of acute liver injury, GSH levels are decreased, and this is significantly recovered upon the administration of CAY10594 at 6 hours post APAP challenge. GSK-3β (Serine 9)/JNK phosphorylation is mainly involved in APAP-induced liver injury. CAY10594 administration strongly blocked GSK-3β (Serine 9)/JNK phosphorylation in the APAP-induced acute liver injury model. Consistently, sustained JNK activation in the cytosol and mitochondria from hepatocytes were also decreased in CAY10594-treated mice. Many types of immune cells are also implicated in APAP-induced liver injury. However, neutrophil and monocyte populations were not different between vehicle- and CAY10594-administered mice which are challenged with APAP. Therapeutic administration of CAY10594 also significantly attenuated liver damage caused by the APAP challenge, eliciting an enhanced survival rate. Taken together, these results indicate that PLD2 is involved in the intrinsic response pathway of hepatocytes driving the pathogenesis of APAP-induced acute liver injury, and PLD2 may therefore represent an important therapeutic target for patients with drug-induced liver injury.
Highlights
Acetaminophen (APAP), an over-the counter drug, is widely used as an analgesic and antipyretic, overdose may cause serious hepatotoxicity due to hepatocellular necrosis[1,2]
We investigated the role of phospholipase D2 (PLD2) on acute liver injury using a CAY10594
APAP-induced liver injury was almost completely blocked by the administration of a CAY10594 in a dose-dependent manner (Fig. 1A)
Summary
Acetaminophen (APAP), an over-the counter drug, is widely used as an analgesic and antipyretic, overdose may cause serious hepatotoxicity due to hepatocellular necrosis[1,2]. Oxidation by cytochrome P450 enzymes becomes important in the metabolism of APAP, and excess NAPQI binds to SH- groups in cellular proteins, causing cell injury[4]. During this process, the glutathione (GSH) supply is exhausted[5]. Recent reports have shown that GSK-3β is an important mediator causing APAP-induced liver injury[9]. It has been reported that phosphatidic acid (PA), a product of PLD enzymatic activity, is elevated during APAP-induced acute liver injury and APAP overdose patients[17]. We examined the role of PLD2 on DILI and the related mechanism of action using a PLD2-selective inhibitor
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