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Aminotriazole alleviates acetaminophen poisoning via downregulating P450 2E1 and suppressing inflammation.

Jing Y, Wu K, Liu J, Ai Q, Ge P, Dai J, Jiang R, Zhou D, Che Q, Wan J, Zhang L - PLoS ONE (2015)

Bottom Line: In mice exposed to APAP, ATZ pretreatment decreased the CAT activities, hydrogen peroxide (H2O2) levels, malondialdehyde (MDA) contents, myeloperoxidase (MPO) levels in liver and reduced TNF-α levels in plasma.In addition, posttreatment with ATZ after APAP challenge decreased the levels of plasma aminotransferases and increased the survival rate of experimental animals.Posttreatment with ATZ had no effects on CYP2E1 expression or JNK phosphorylation, but it significantly decreased the levels of plasma TNF-α.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, China.

ABSTRACT
Aminotriazole (ATZ) is commonly used as a catalase (CAT) inhibitor. We previously found ATZ attenuated oxidative liver injury, but the underlying mechanisms remain unknown. Acetaminophen (APAP) overdose frequently induces life-threatening oxidative hepatitis. In the present study, the potential hepatoprotective effects of ATZ on oxidative liver injury and the underlying mechanisms were further investigated in a mouse model with APAP poisoning. The experimental data indicated that pretreatment with ATZ dose- and time-dependently suppressed the elevation of plasma aminotransferases in APAP exposed mice, these effects were accompanied with alleviated histological abnormality and improved survival rate of APAP-challenged mice. In mice exposed to APAP, ATZ pretreatment decreased the CAT activities, hydrogen peroxide (H2O2) levels, malondialdehyde (MDA) contents, myeloperoxidase (MPO) levels in liver and reduced TNF-α levels in plasma. Pretreatment with ATZ also downregulated APAP-induced cytochrome P450 2E1 (CYP2E1) expression and JNK phosphorylation. In addition, posttreatment with ATZ after APAP challenge decreased the levels of plasma aminotransferases and increased the survival rate of experimental animals. Posttreatment with ATZ had no effects on CYP2E1 expression or JNK phosphorylation, but it significantly decreased the levels of plasma TNF-α. Our data indicated that the LD50 of ATZ in mice was 5367.4 mg/kg body weight, which is much higher than the therapeutic dose of ATZ in the present study. These data suggested that ATZ might be effective and safe in protect mice against APAP-induced hepatotoxicity, the beneficial effects might resulted from downregulation of CYP2E1 and inhibiton of inflammation.

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Related in: MedlinePlus

Pretreatment with ATZ decreased the mortality induced by APAP.Mice were pretreated with vehicle or various doses of ATZ (125 mg/kg, 250 mg/kg, 500 mg/kg) before APAP exposure. Survival was monitored and the percent survival rate was expressed as Kaplan-Meier survival curves (n = 20). #P<0.05, ##P<0.01, as compared with the APAP group.
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pone.0122781.g003: Pretreatment with ATZ decreased the mortality induced by APAP.Mice were pretreated with vehicle or various doses of ATZ (125 mg/kg, 250 mg/kg, 500 mg/kg) before APAP exposure. Survival was monitored and the percent survival rate was expressed as Kaplan-Meier survival curves (n = 20). #P<0.05, ##P<0.01, as compared with the APAP group.

Mentions: The levels of ALT and AST, widely used as quantitative biochemical markers of hepatocellular damage [23], increased significantly after APAP challenge, but the elevation of these aminotransferases was suppressed in mice pretreated with ATZ in a dose and time-dependent manner (Fig 1). The histological examination found that intraperitoneal injection of APAP resulted in obvious histological abnormalities, including massive cell necrosis and extensive hemorrhage in liver tissues. Consistent with the decreased elevation of aminotransferases, pretreatment with ATZ markedly attenuated APAP-induced histological lesions (Fig 2). Our data also showed that pretreatment with ATZ dose-dependently improved the survival rate of APAP-challenged mice (Fig 3). In addition, the plasma aminotransferases level (Fig 1), the hepatic histological architecture (Fig 2) and the survival rate (data not shown) in mice treated with ATZ alone were not different from those of the control mice.


Aminotriazole alleviates acetaminophen poisoning via downregulating P450 2E1 and suppressing inflammation.

Jing Y, Wu K, Liu J, Ai Q, Ge P, Dai J, Jiang R, Zhou D, Che Q, Wan J, Zhang L - PLoS ONE (2015)

Pretreatment with ATZ decreased the mortality induced by APAP.Mice were pretreated with vehicle or various doses of ATZ (125 mg/kg, 250 mg/kg, 500 mg/kg) before APAP exposure. Survival was monitored and the percent survival rate was expressed as Kaplan-Meier survival curves (n = 20). #P<0.05, ##P<0.01, as compared with the APAP group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401561&req=5

pone.0122781.g003: Pretreatment with ATZ decreased the mortality induced by APAP.Mice were pretreated with vehicle or various doses of ATZ (125 mg/kg, 250 mg/kg, 500 mg/kg) before APAP exposure. Survival was monitored and the percent survival rate was expressed as Kaplan-Meier survival curves (n = 20). #P<0.05, ##P<0.01, as compared with the APAP group.
Mentions: The levels of ALT and AST, widely used as quantitative biochemical markers of hepatocellular damage [23], increased significantly after APAP challenge, but the elevation of these aminotransferases was suppressed in mice pretreated with ATZ in a dose and time-dependent manner (Fig 1). The histological examination found that intraperitoneal injection of APAP resulted in obvious histological abnormalities, including massive cell necrosis and extensive hemorrhage in liver tissues. Consistent with the decreased elevation of aminotransferases, pretreatment with ATZ markedly attenuated APAP-induced histological lesions (Fig 2). Our data also showed that pretreatment with ATZ dose-dependently improved the survival rate of APAP-challenged mice (Fig 3). In addition, the plasma aminotransferases level (Fig 1), the hepatic histological architecture (Fig 2) and the survival rate (data not shown) in mice treated with ATZ alone were not different from those of the control mice.

Bottom Line: In mice exposed to APAP, ATZ pretreatment decreased the CAT activities, hydrogen peroxide (H2O2) levels, malondialdehyde (MDA) contents, myeloperoxidase (MPO) levels in liver and reduced TNF-α levels in plasma.In addition, posttreatment with ATZ after APAP challenge decreased the levels of plasma aminotransferases and increased the survival rate of experimental animals.Posttreatment with ATZ had no effects on CYP2E1 expression or JNK phosphorylation, but it significantly decreased the levels of plasma TNF-α.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, China.

ABSTRACT
Aminotriazole (ATZ) is commonly used as a catalase (CAT) inhibitor. We previously found ATZ attenuated oxidative liver injury, but the underlying mechanisms remain unknown. Acetaminophen (APAP) overdose frequently induces life-threatening oxidative hepatitis. In the present study, the potential hepatoprotective effects of ATZ on oxidative liver injury and the underlying mechanisms were further investigated in a mouse model with APAP poisoning. The experimental data indicated that pretreatment with ATZ dose- and time-dependently suppressed the elevation of plasma aminotransferases in APAP exposed mice, these effects were accompanied with alleviated histological abnormality and improved survival rate of APAP-challenged mice. In mice exposed to APAP, ATZ pretreatment decreased the CAT activities, hydrogen peroxide (H2O2) levels, malondialdehyde (MDA) contents, myeloperoxidase (MPO) levels in liver and reduced TNF-α levels in plasma. Pretreatment with ATZ also downregulated APAP-induced cytochrome P450 2E1 (CYP2E1) expression and JNK phosphorylation. In addition, posttreatment with ATZ after APAP challenge decreased the levels of plasma aminotransferases and increased the survival rate of experimental animals. Posttreatment with ATZ had no effects on CYP2E1 expression or JNK phosphorylation, but it significantly decreased the levels of plasma TNF-α. Our data indicated that the LD50 of ATZ in mice was 5367.4 mg/kg body weight, which is much higher than the therapeutic dose of ATZ in the present study. These data suggested that ATZ might be effective and safe in protect mice against APAP-induced hepatotoxicity, the beneficial effects might resulted from downregulation of CYP2E1 and inhibiton of inflammation.

Show MeSH
Related in: MedlinePlus