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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

Posttreatment with ATZ suppressed the elevation of plasma aminotransferases induced by APAP.Mice were treated with vehicle or ATZ (500 mg/kg) at 1 h (A and D), 2 h (B and E) or 4 h (C and F) after APAP exposure. The plasma levels of alanine aminotransferase (ALT, A-C) and aspartate aminotransferase (AST, D-F) were determined at 8 h after LPS/D-Gal exposure. Data were expressed as mean ± SD, n = 8. NSP>0.05, #P<0.05, ##P<0.01, as compared with the APAP group.
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pone.0122781.g008: Posttreatment with ATZ suppressed the elevation of plasma aminotransferases induced by APAP.Mice were treated with vehicle or ATZ (500 mg/kg) at 1 h (A and D), 2 h (B and E) or 4 h (C and F) after APAP exposure. The plasma levels of alanine aminotransferase (ALT, A-C) and aspartate aminotransferase (AST, D-F) were determined at 8 h after LPS/D-Gal exposure. Data were expressed as mean ± SD, n = 8. NSP>0.05, #P<0.05, ##P<0.01, as compared with the APAP group.

Mentions: Since the pre-insult treatment protocol is different from clinic settings and seems unrealistic in clinical treatment, the pharmacological efficiency of ATZ treated with clinically relevant post-insult administration strategy was also tested. The experimental data indicated that ATZ administered at 1 h or 2 h after APAP challenged could also decrease the elevation of ALT and AST. However, treatment with ATZ at 4 h after APAP exposure had no obvious effect on the levels of ALT and AST (Fig 8A–8F). In addition, the administration of ATZ at 1 h or 2 h after APAP exposure significantly improved the survival rate of mice (Fig 9). The data also indicated that posttreatment with ATZ significantly suppressed APAP-induced production of TNF-α but it had no effects on the levels of phosphorylated JNK or CYP2E1 (Fig 10).


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)

Posttreatment with ATZ suppressed the elevation of plasma aminotransferases induced by APAP.Mice were treated with vehicle or ATZ (500 mg/kg) at 1 h (A and D), 2 h (B and E) or 4 h (C and F) after APAP exposure. The plasma levels of alanine aminotransferase (ALT, A-C) and aspartate aminotransferase (AST, D-F) were determined at 8 h after LPS/D-Gal exposure. Data were expressed as mean ± SD, n = 8. NSP>0.05, #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.g008: Posttreatment with ATZ suppressed the elevation of plasma aminotransferases induced by APAP.Mice were treated with vehicle or ATZ (500 mg/kg) at 1 h (A and D), 2 h (B and E) or 4 h (C and F) after APAP exposure. The plasma levels of alanine aminotransferase (ALT, A-C) and aspartate aminotransferase (AST, D-F) were determined at 8 h after LPS/D-Gal exposure. Data were expressed as mean ± SD, n = 8. NSP>0.05, #P<0.05, ##P<0.01, as compared with the APAP group.
Mentions: Since the pre-insult treatment protocol is different from clinic settings and seems unrealistic in clinical treatment, the pharmacological efficiency of ATZ treated with clinically relevant post-insult administration strategy was also tested. The experimental data indicated that ATZ administered at 1 h or 2 h after APAP challenged could also decrease the elevation of ALT and AST. However, treatment with ATZ at 4 h after APAP exposure had no obvious effect on the levels of ALT and AST (Fig 8A–8F). In addition, the administration of ATZ at 1 h or 2 h after APAP exposure significantly improved the survival rate of mice (Fig 9). The data also indicated that posttreatment with ATZ significantly suppressed APAP-induced production of TNF-α but it had no effects on the levels of phosphorylated JNK or CYP2E1 (Fig 10).

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