Irbesartan mitigates acute liver injury, oxidative stress, and apoptosis induced by acetaminophen in mice

Abstract

Hepatotoxicity induced by acetaminophen (APAP)-overdose is a major concern in clinical practice. In the present work, the detoxifying effect of irbesartan (Irb) on the APAP-induced acute liver injury was evaluated in mice. Induction of acute liver injury in mice was established by a single intraperitoneal (IP) injection of APAP (0.5 g/kg), then mice were injected with Irb (50 or 75 mg/kg, IP), each given twice at 1 and 12 hours post APAP injection. Liver functions, hepatic oxidative and nitrosative stress markers, and liver histopathology were determined after 24 hours. Hepatic cytochrome P450 2E1 (CYP2E1), nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) levels were also estimated. Immunohistochemical evaluations of hepatic expression of phosphorylated NF-kB and active caspase-3 were assigned. Irb treatment attenuated APAP-induced acute liver injury. Irb suppressed APAP-caused elevation of liver enzymes as well as oxidative and nitrosative stress in liver tissues as evidenced by the decrease in hepatic CYP2E1 expression and hepatic levels of malondialdehyde and nitric oxide in addition to the elevated hepatic superoxide dismutase activity and reduced glutathione concentration. Also, Irb mitigated APAP-induced inflammation in liver tissues via decreasing the expression of hepatic NF-κB, phosphorylated NF-κB and TNF-α, and attenuated hepatic apoptosis via decreasing Bax/Bcl-2 ratio and caspase 3 expression and activation. Also, Irb mitigated the APAP-induced histopathological changes in liver specimens. These data suggested that Irb ameliorates APAP-induced acute liver injury through antioxidant, anti-inflammatory, and antiapoptotic activities.

Protective Effects of Irbesartan, an Angiotensin Receptor Blocker with PPARγ Agonistic Activity, against Estradiol Benzoate-Induced Endometrial Hyperplasia and Atypia in Female Rats via Modulation of TNFα/Survivin Pathway

“…In the current study, IRB administration afforded protection to the uterus against EB-induced oxidative stress. Consistent with this result, several previous studies demonstrated similar findings relating to the ability of IRB to decrease oxidative stress through a significant reduction in MDA level with a significant increase in SOD activity [24,25], may be partly through AT1R blockade, as Ang II can result in oxidative stress [32], and PPARγ agonistic activity [33].…”

“…This directed our attention to examine the possible unexplored protective mechanisms of IRB, an AT1R blocker with PPARγ agonistic activity [ 23 ], in EH. For example, IRB shows anti-inflammatory and antioxidant properties [ 24 , 25 , 26 ], two actions that are expected to be efficacious in the prevention of EH. The results showed that EB succeeded in the induction of EH as evidenced by the significant increase in uterine weights, MDA, TNFα, survivin with a concomitant decrease in SOD, cleaved caspase 3, IL10, and PPARγ, besides typical histopathological features of EH and atypia.…”

Diacerein ameliorates acetaminophen hepatotoxicity in rats via inhibiting HMGB1/TLR4/NF-κB and upregulating PPAR-γ signal

“…Acetaminophen (APAP) is widely utilized as an over-the-counter drug for treating inflammation, fever, as well as pain [ 1 ]. APAP is currently the main antipyretic and analgesic drug recommended by several studies over non-steroidal anti-inflammatory drugs (NSAIDs) used to manage fever and pain associated with the pandemic infection of coronavirus 2019 (COVID-19).…”

“…This assumption could cause a possible misuse of acetaminophen, which is considered the major cause behind drug-induced liver injury (DILI) worldwide. [ 1 – 3 ]. Although N -acetylcysteine (NAC) is the current drug used to protect against liver injury induced by APAP, it is only effective when given an early period of APAP ingestion and associated with adverse effects such as nausea, vomiting, allergic reactions, and headaches [ 4 ].…”

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

“…Also, Wu et al [27] revealed that increased caspase-3 expression in APAP treated mice was observed around CV. In addition, Irbesartan mitigated APAP-induced caspase-3 expression in mice model [28]. Similarly, Li et al [29] showed that apoptosis, induced by activated HSCs, is characterized by increased caspase-3 in-vitro.…”