A sinalização parácrina por ATP/ADP é detrimental durante a morte celular estéril induzida por paracetamol

Abstract

The liver is an essential organ to maintaining the body homeostasis. Among its many critical roles, resides the important function of hepatic metabolism of chemicals, toxins and drugs. Considering the important functions performed by the liver, it is expected that the hepatic diseases entail large losses to illness people. It is therefore important to amplify the knowledge on this field. Paracetamol (APAP) overdose causes liver injury and is the major cause of acute liver failure (ALF) in the United States and UK. It is well known that during the acute cell death, such as induced by APAP, an imbalance in the ionic cell dynamics is observed (especially in mitochondria), which includes the dysregulation in the intracellular calcium content. Such alteration can, ultimately, promote cell death by necrosis, releasing intracellular contents, including DNA, HSP, mitochondrial products and ATP. Interesting, ATP induces calcium pulses in cultured hepatocytes, although it is not determined how the purinergic signaling and the calcium signaling are co-related in the context of necrosis, as well as its individual role in the sterile cell death mechanism induced by paracetamol. In this context, we have investigated if the extracellular ATP release during APAP-induced necrosis consists in a reverberating cell death feature, as well to elucidate the mechanisms by which purines modulate hepatocyte mitosis cycle. We have shown that the incubation of a hepatocytic linage (HepG2) with paracetamol promotes cellular death, increasing ATP concentration in the culture medium, and consequently the hyper-responsiveness to this purine. Interesting, the ATP destruction (by an ATPase) reverted significantly the cell death induced by APAP, also by using a in vivo model of ALF. Thus, the incubation with adenosine reverted the cell death induced by APAP. Our data suggest that the ATP release (and its metabolite ADP) is detrimental during the acute cell death and the final metabolism of ATP until adenosine may be a protective mechanism against the acute cell death amplification, putting forward the future exploration of this signaling pathway in the therapeutics.