Boldine treatment protects acetaminophen‐induced liver inflammation and acute hepatic necrosis in mice

Abstract

Drug‐induced liver injury (DILI) is a frequent cause responsible for acute liver failure (ALF). Acetaminophen (APAP) is a known hepatotoxin predictably causing intrinsic DILI. At high doses, APAP causes acute liver necrosis and responsible for ALF and liver transplant cases in 50% and 20% of patients, respectively, in the United States alone. Oxidative stress and glutathione depletion are implicated in APAP‐induced liver necrosis. Boldine, a plant‐derived compound is shown to have promising antioxidant potential. Therefore, this study investigates the protective effect of boldine against APAP‐induced acute hepatic necrosis in mice. A single toxic dose of APAP (300 mg/kg b.w. p.o.) was administered in overnight‐fasted mice to induce acute liver necrosis. Separately, APAP + boldine and APAP + N‐acetylcysteine (NAC) simultaneous treatments were also given. Serum transaminases and reduced glutathione, enzymic antioxidants, tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), and, IL‐6 were evaluated in liver tissue. Acute APAP intoxication significantly elevated serum marker enzymes of hepatotoxicity. APAP administration increased lipid peroxidation, TNF‐α, IL‐1β, and IL‐6 protein expressions. The enzymic antioxidants and reduced glutathione levels were decreased in liver tissue of APAP intoxicated mice. Boldine and NAC simultaneous treatments prevented APAP‐induced oxidative stress, inflammation, and necrosis. The results of this study suggest the crucial role of boldine to protect against APAP induced hepatotoxicity by virtue of its antioxidant and anti‐inflammatory properties.

Syringic acid and silymarin concurrent administration inhibits sodium valproate‐induced liver injury in rats

“…Previous studies have shown that administration of more than 300 mg/kg/day of SV can cause hepatotoxic markers enzymes (AST, ALT, and ALP) elevation and micro‐anatomical changes in liver tissue of rats 10,35 . The AST, ALT, and ALP enzymes are confined to hepatocytes, whenever there is a hepatocellular degeneration caused by certain drug metabolites, liver cells liberate these enzymes into the systemic circulation 36,37 . Clinically, AST, ALT, and ALP elevations have been reported as one of the common phenomena of DILI 38 .…”

“…10,35 The AST, ALT, and ALP enzymes are confined to hepatocytes, whenever there is a hepatocellular degeneration caused by certain drug metabolites, liver cells liberate these enzymes into the systemic circulation. 36,37 Clinically, AST, ALT, and ALP elevations have been reported as one of the common phenomena of DILI. 38 In clinical subjects, SV has been known to cause hepatocellular degeneration.…”

Detection of Synergistic Interaction on an Additive Scale Between Two Drugs on Abnormal Elevation of Serum Alanine Aminotransferase Using Machine-Learning Algorithms

“…However, there was no association between the individual effect of this drug and the risk of abnormal elevation of ALT in the logistic LASSO regression model. Acetaminophen is a known hepatotoxin causing intrinsic DILI, which is related to increasing dose ( Ezhilarasan and Raghunandhakumar, 2021 ). It is proposed that the safe dose of acetaminophen to avoid liver injury is ≤ 4 g/day for an adult ( Jaeschke, 2015 ), and the maximum approved dose of acetaminophen is 4 g/day in Japan.…”

The immunological mechanisms and therapeutic potential in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity

“…Several intervention studies confirmed that TNF expression alters the severity of AILI [ 89 , 166 , 191 , 226 , 227 ]. Combination therapy of boldine and NAC significantly reduces the expression of inflammatory markers, including TNF-α, IL-1β, and IL-6 [ 228 ]. Poria cocos polysaccharides pretreatment attenuates AILI by decreasing the expression of TNF-β and tumor necrosis factor receptor (TNFsR)-I [ 229 ].…”