ArticleFrontiers in pharmacology2019
Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu.
Article in Frontiers in pharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 22 citations in OpenAlex.
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- Electrochemical Probing of Human Liver Subcellular S9 Fractions for Drug Metabolite Synthesis.Metabolites · 2024Article
- Hepa-ToxMOA: a pathway-screening method for evaluating cellular stress and hepatic metabolic-dependent toxicity of natural products.Scientific reports · 2024Article
- Anti-Cryptosporidial Drug-Discovery Challenges and Existing Therapeutic Avenues: A "One-Health" Concern.Life (Basel, Switzerland) · 2024Review
- The roles of CYP2C19 and CYP3A4 in the in vitro metabolism of β-eudesmol in human liver: Reaction phenotyping and enzyme kinetics.Pharmacology research & perspectives · 2023Article
- Toad venom-derived bufadienolides and their therapeutic application in prostate cancers: Current status and future directions.Frontiers in chemistry · 2023Review
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- Identification of potent anti-Cryptosporidium new drug leads by screening traditional Chinese medicines.PLoS neglected tropical diseases · 2022Article
- Identification of Potential Cytochrome P450 3A5 Inhibitors: An Extensive Virtual Screening through Molecular Docking, Negative Image-Based Screening, Machine Learning and Molecular Dynamics Simulation Studies.International journal of molecular sciences · 2022Article
- Discovery of human pancreatic lipase inhibitors from root ofJournal of pharmaceutical analysis · 2022Article
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- Protective effects of organic extracts ofNeural regeneration research · 2020Article
- Elucidation of the Differences in Cinobufotalin's Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein.Frontiers in pharmacology · 2019Article
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Bufotalin (BFT), one of the naturally occurring bufodienolides, has multiple pharmacological and toxicological effects including antitumor activity and cardiotoxicity. This study aimed to character the metabolic pathway(s) of BFT and to identify the key drug metabolizing enzyme(s) responsible for hepatic metabolism of BFT in human, as well as to explore the related molecular mechanism of enzymatic selectivity. The major metabolite of BFT in human liver microsomes (HLMs) was fully identified as 5β-hydroxylbufotalin by LC-MS/MS and NMR techniques. Reaction phenotyping and chemical inhibition assays showed that CYP3A4 and CYP3A5 were key enzymes responsible for BFT 5β-hydroxylation. Kinetic analyses demonstrated that BFT 5β-hydroxylation in both HLMs and human CYP3A4 followed the biphasic kinetics, while BFT 5β-hydroxylation in CYP3A5 followed substrate inhibition kinetics. Furthermore, molecular docking simulations showed that BFT could bind on two different ligand-binding sites on both CYP3A4 and CYP3A5, which partially explained the different kinetic behaviors of BFT in CYP3A4 and CYP3A5. These findings are very helpful for elucidating the phase I metabolism of BFT in human and for deeper understanding the key interactions between CYP3A enzymes and bufadienolides, as well as for the development of bufadienolide-type drugs with improved pharmacokinetic and safety profiles.
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