ArticleArchives of toxicology2021
Lung injury induced by pyrrolizidine alkaloids depends on metabolism by hepatic cytochrome P450s and blood transport of reactive metabolites.
Article in Archives of toxicology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 42 citations in OpenAlex.
- Red blood cell damage defines the etiology of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids.Acta pharmaceutica Sinica. B · 2026Article
- Monocrotaline toxicity in rats: decreased lung retinol and elevated alpha-tocopherol levels in lung and liver.Journal of nutritional science · 2026Article
- The role of natural products targeting macrophage polarization in sepsis-induced lung injury.Chinese medicine · 2025Review
- Atrial cardiomyocytes contribute to the inflammatory status associated with atrial fibrillation in right heart disease.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2024Article
- The siRNA-mediated knockdown of AP-1 restores the function of the pulmonary artery and the right ventricle by reducing perivascular and interstitial fibrosis and key molecular players in cardiopulmonary disease.Journal of translational medicine · 2024Article
- INTEDE 2.0: the metabolic roadmap of drugs.Nucleic acids research · 2024Article
- Equine Crofton Weed (Animals : an open access journal from MDPI · 2023Review
- Potency ranking of pyrrolizidine alkaloids in metabolically competent human liver cancer cells and primary human hepatocytes using a genotoxicity test battery.Archives of toxicology · 2023Article
- Targeting erythrocyte-mediated hypoxia to alleviate lung injury induced by pyrrolizidine alkaloids.Archives of toxicology · 2023Article
- Structure-Dependent Toxicokinetics of Selected Pyrrolizidine Alkaloids In Vitro.International journal of molecular sciences · 2022Article
- Article
- Electrogenerated chemiluminescence of a Ru(bpy)RSC advances · 2022Article
- Assessing cytochrome P450 function using genetically engineered mouse models.Advances in pharmacology (San Diego, Calif.) · 2022Review
- Liquorice Extract and 18β-Glycyrrhetinic Acid Protect Against Experimental Pyrrolizidine Alkaloid-Induced Hepatotoxicity in Rats Through Inhibiting Cytochrome P450-Mediated Metabolic Activation.Frontiers in pharmacology · 2022Article
- The key role of gut-liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity.Acta pharmaceutica Sinica. B · 2021Article
- Developing urinary pyrrole-amino acid adducts as non-invasive biomarkers for identifying pyrrolizidine alkaloids-induced liver injury in human.Archives of toxicology · 2021Article
- Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update.International journal of molecular sciences · 2021Review
- Pyrrolizidine alkaloid-induced transcriptomic changes in rat lungs in a 28-day subacute feeding study.Archives of toxicology · 2021Article
- Metabolism-mediated cytotoxicity and genotoxicity of pyrrolizidine alkaloids.Archives of toxicology · 2021Review
- Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities.Frontiers in pharmacology · 2021Review
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Pyrrolizidine alkaloids (PAs) are common phytotoxins with both hepatotoxicity and pneumotoxicity. Hepatic cytochrome P450 enzymes are known to bioactivate PAs into reactive metabolites, which can interact with proteins to form pyrrole-protein adducts and cause intrahepatic cytotoxicity. However, the metabolic and initiation biochemical mechanisms underlying PA-induced pneumotoxicity remain unclear. To investigate the in vivo metabolism basis for PA-induced lung injury, this study used mice with conditional deletion of the cytochrome P450 reductase (Cpr) gene and resultant tissue-selective ablation of microsomal P450 enzyme activities. After oral exposure to monocrotaline (MCT), a pneumotoxic PA widely used to establish animal lung injury models, liver-specific Cpr-null (LCN) mice, but not extrahepatic Cpr-low (xh-CL) mice, had significantly lower level of pyrrole-protein adducts in the serum, liver and lungs compared with wild-type (WT) mice. While MCT-exposed LCN mice had significantly higher blood concentration of intact MCT, compared to MCT-exposed WT or xh-CL mice. Consistent with the MCT in vivo bioactivation data, MCT-induced lung injury, represented by vasculature damage, in WT and xh-CL mice but not LCN mice. Furthermore, reactive metabolites of MCT were confirmed to exist in the blood efflux from the hepatic veins of MCT-exposed rats. Our results provide the first mode-of-action evidence that hepatic P450s are essential for the bioactivation of MCT, and blood circulating reactive metabolites of MCT to the lung causes pneumotoxicity. Collectively, this study presents the scientific basis for the application of MCT in animal lung injury models, and more importantly, warrants public awareness and further investigations of lung diseases associated with exposure to not only MCT but also different PAs.
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