Loss of RAR-α and RXR-α and enhanced caspase-3-dependent apoptosis in N-acetyl-p-aminophenol-induced liver injury in mice is tissue factor dependent
Mohamed Sadek Abdel-Bakky1,2,*, Gouda Kamel Helal1,3, El-Sayed Mohamed El-Sayed1, Elham Amin4,5, Abdulmajeed Alqasoumi6, Ahmad Alhowail2, Eman Sayed Said Abdelmoti2,7, and Ahmed Saad Saad8
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt,2Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 52471, Saudi Arabia, 3Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt,4Department of Pharmacognosy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt, 5Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah 52471, Saudi Arabia, 6Department of Pharmacy Practice, College of Pharmacy, Qassim University, Buraydah 52471, Saudi Arabia,7Department of Clinical Pharmacology, Faculty of Medicine, Fayoum University, Fayoum 63514, Egypt, 8Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said 42511, Egypt
Tissue factor (TF) activates the coagulation system and has an important role in the pathogenesis of various diseases. Our previous study stated that retinoid receptors (RAR-α and RXR-α) are released as a lipid droplet in monocrotaline/ lipopolysaccharide-induced idiosyncratic liver toxicity in mice. Herein, the interdependence between the release of retinoid receptors RAR-α and RXR-α and TF in Nacetyl-p-aminophenol (APAP)-induced mice liver toxicity, is investigated. Serum alanine transaminase (ALT) level, platelet and white blood cells (WBCs) counts, protein expression of fibrin, TF, cyclin D1 and cleaved caspase-3 in liver tissues are analyzed. In addition, histopathological evaluation and survival study are also performed. The results indicate that using of TF-antisense (TF-AS) deoxyoligonucleotide (ODN) injection (6 mg/kg), to block TF protein synthesis, significantly restores the elevated level of ALT and WBCs and corrects thrombocytopenia in mice injected with APAP. TF-AS prevents the peri-central overexpression of liver TF, fibrin, cyclin D1 and cleaved caspase- 3. The release of RXR-α and RAR-α droplets, in APAP treated sections, is inhibited upon treatment with TF-AS. In conclusion, the above findings designate that the released RXR-α and RAR-α in APAP liver toxicity is TF dependent. Additionally, the enhancement of cyclin D1 to caspase-3-dependent apoptosis can be prevented by blocking of TF protein synthesis.
Keywords: Acetaminophen, Retinoid A receptor alpha, Retinoid X receptor alpha, Thromboplastin, Tissue factor antisense