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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 level of CYP2E1 in APAP exposed mice.Mice were treated with vehicle or ATZ (500 mg/kg) at 30 min before APAP exposure. Liver samples were harvested at 8 h after APAP exposure. The levels of CYP2E1 were determined by Western blot analysis. (A) The bands of CYP2E1 and β-actin were indicated by arrows. (B) Western blots were scanned by densitometry and data presented as relative intensity units. Data were expressed as mean ± SD, n = 8. NSP>0.05, * P<0.05, as compared with the CON group; #P<0.05, as compared with the APAP group.
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pone.0122781.g007: Pretreatment with ATZ decreased the level of CYP2E1 in APAP exposed mice.Mice were treated with vehicle or ATZ (500 mg/kg) at 30 min before APAP exposure. Liver samples were harvested at 8 h after APAP exposure. The levels of CYP2E1 were determined by Western blot analysis. (A) The bands of CYP2E1 and β-actin were indicated by arrows. (B) Western blots were scanned by densitometry and data presented as relative intensity units. Data were expressed as mean ± SD, n = 8. NSP>0.05, * P<0.05, as compared with the CON group; #P<0.05, as compared with the APAP group.

Mentions: APAP is metabolically activated mainly by CYP2E1 [28]. The present study showed that APAP-challenge markedly increased the contents of hepatic CYP2E1 protein. Treatment with ATZ significantly suppressed the induction of CYP2E1 (Fig 7).


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 level of CYP2E1 in APAP exposed mice.Mice were treated with vehicle or ATZ (500 mg/kg) at 30 min before APAP exposure. Liver samples were harvested at 8 h after APAP exposure. The levels of CYP2E1 were determined by Western blot analysis. (A) The bands of CYP2E1 and β-actin were indicated by arrows. (B) Western blots were scanned by densitometry and data presented as relative intensity units. Data were expressed as mean ± SD, n = 8. NSP>0.05, * P<0.05, as compared with the CON group; #P<0.05, as compared with the APAP group.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0122781.g007: Pretreatment with ATZ decreased the level of CYP2E1 in APAP exposed mice.Mice were treated with vehicle or ATZ (500 mg/kg) at 30 min before APAP exposure. Liver samples were harvested at 8 h after APAP exposure. The levels of CYP2E1 were determined by Western blot analysis. (A) The bands of CYP2E1 and β-actin were indicated by arrows. (B) Western blots were scanned by densitometry and data presented as relative intensity units. Data were expressed as mean ± SD, n = 8. NSP>0.05, * P<0.05, as compared with the CON group; #P<0.05, as compared with the APAP group.
Mentions: APAP is metabolically activated mainly by CYP2E1 [28]. The present study showed that APAP-challenge markedly increased the contents of hepatic CYP2E1 protein. Treatment with ATZ significantly suppressed the induction of CYP2E1 (Fig 7).

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