Shiyun Pu1, Lin Ren1, Qinhui Liu2, Jiangying Kuang1, Jing Shen1, Shihai Cheng1, Yuwei Zhang3, Wei Jiang4, Zhiyong Zhang1, Changtao Jiang5, Jinhan He1,2. 1. Department of Pharmacy, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China. 2. Laboratory of Clinical Pharmacy and Adverse Drug Reaction, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China. 3. Division of Endocrinology and Metabolism, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China. 4. Molecular Medicine Research Center, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China. 5. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
Abstract
BACKGROUND AND PURPOSE: Paracetamol (acetaminophen) is the most widely used over-the-counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5-Lipoxygenase (5-LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5-LO could protect mice against paracetamol-induced hepatic toxicity. EXPERIMENTAL APPROACH: Both genetic deletion and pharmacological inhibition of 5-LO in C57BL/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&E staining, and real-time PCR were used to assess liver toxicity. KEY RESULTS: Deletion or pharmacological inhibition of 5-LO in mice markedly ameliorated paracetamol-induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5-LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro-toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5-LO(-/-) mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR α, a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5-LO(-/-) mice. CONCLUSIONS AND IMPLICATIONS: The activity of 5-LO may play a critical role in paracetamol-induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress.
BACKGROUND AND PURPOSE:Paracetamol (acetaminophen) is the most widely used over-the-counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5-Lipoxygenase (5-LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5-LO could protect mice against paracetamol-induced hepatic toxicity. EXPERIMENTAL APPROACH: Both genetic deletion and pharmacological inhibition of 5-LO in C57BL/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&E staining, and real-time PCR were used to assess liver toxicity. KEY RESULTS: Deletion or pharmacological inhibition of 5-LO in mice markedly ameliorated paracetamol-induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5-LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro-toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5-LO(-/-) mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR α, a nuclear receptor that confers resistance to paracetamoltoxicity, was activated in 5-LO(-/-) mice. CONCLUSIONS AND IMPLICATIONS: The activity of 5-LO may play a critical role in paracetamol-induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress.
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