Loss of BOK Has a Minor Impact on Acetaminophen Overdose-Induced Liver Damage in Mice

Samara Naim,Daniel Bachmann,Simone De Brot,Yuniel Fernandez-Marrero,Thomas Kaufmann

doi:10.3390/ijms22063281

Abstract

Acetaminophen (APAP) is one of the most commonly used analgesic and anti-pyretic drugs, and APAP intoxication is one of the main reasons for liver transplantation following liver failure in the Western world. While APAP poisoning ultimately leads to liver necrosis, various programmed cell death modalities have been implicated, including ER stress-triggered apoptosis. The BCL-2 family member BOK (BCL-2-related ovarian killer) has been described to modulate the unfolded protein response and to promote chemical-induced liver injury. We therefore investigated the impact of the loss of BOK following APAP overdosing in mice. Surprisingly, we observed sex-dependent differences in the activation of the unfolded protein response (UPR) in both wildtype (WT) and Bok-/- mice, with increased activation of JNK in females compared with males. Loss of BOK led to a decrease in JNK activation and a reduced percentage of centrilobular necrosis in both sexes after APAP treatment; however, this protection was more pronounced in Bok-/- females. Nevertheless, serum ALT and AST levels of Bok-/- and WT mice were comparable, indicating that there was no major difference in the overall outcome of liver injury. We conclude that after APAP overdosing, loss of BOK affects initiating signaling steps linked to ER stress, but has a more minor impact on the outcome of liver necrosis. Furthermore, we observed sex-dependent differences that might be worthwhile to investigate.

Highlights

IntroductionPara-(Acetylamino)phenol (acetaminophen, paracetamol, referred to as APAP)is one of the most commonly used antipyretic and analgesic drugs in the world [1,2]
Para-(Acetylamino)phenolis one of the most commonly used antipyretic and analgesic drugs in the world [1,2]
Since we previously found that BCL-2-related ovarian killer (BOK)-deficient cells (HCT116 and HepG2) and liver lysates derived from Bok-/mice show a higher baseline expression of p53 at both the transcriptional and protein levels [40,45], we tested p53 expression in the liver after APAP treatment by RT-Quantitative RT-PCR (qPCR)

Summary

Introduction

Para-(Acetylamino)phenol (acetaminophen, paracetamol, referred to as APAP)is one of the most commonly used antipyretic and analgesic drugs in the world [1,2]. As an over-the-counter obtainable drug, excessive self-medication—intentional (due to suicide attempts) or unintentional (by the use of combination products containing APAP)—is the main cause of APAP-intoxication and accounts for ~50% of all acute liver failure (ALF) cases in the Western world [1,2,3,4]. While the main portion of APAP is readily conjugated with glucuronic acid or sulphate and excreted with the urine, only a small percentage (~10%) is metabolized by cytochrome P450 (predominantly CYP2E1 and CYP1A2), leading to the formation of the highly reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI) [2,4,6,7]. If GSH stores are depleted, a situation encountered upon APAP overdosing, unconjugated NAPQI binds and reacts with cellular, preferentially mitochondrial proteins, leading to mitochondrial dysfunction and cell death [6]. It has been described that female mice are less susceptible to APAP hepatotoxicity compared to male mice [8,9], due to an accelerated

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Conclusion