Mechanism-based inactivation of cytochrome P450 2D6 by Notopterol

Fu, Yao; Tian, Xiaoxiao; Han, Lingling; Li, Yilin; Peng, Ying; Zheng, Jiang

doi:10.1016/j.cbi.2020.109053

Cited by 7 publications

(6 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, we are unable to exclude the involvement of epoxide 2 in the formation of conjugate 6. Our early study demonstrated that notopterol inactivated CYP2D6, 26 while XTT was found to inactivate CYP1A2 in the present study. The interesting findings may result from the difference in the side chain since the two furanocoumarins share the same structural core.…”

Section: ■ Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanistic Study of Xanthotoxin-Mediated Inactivation of CYP1A2 and Related Drug–Drug Interaction with Tacrine

Ran

Liao

Wang

et al. 2023

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

Xanthotoxin (XTT) is a biologically active furanocoumarin widely present in foods and plants. The present study is designed to systematically investigate the enzymatic interaction of XTT with CYP1A2, along with pharmacokinetic alteration of tacrine resulting from the co-administration of XTT. The results showed that XTT induced a time-, concentration-, and NADPH-dependent inhibition of CYP1A2, and the inhibition was irreversible. Coincubation of glutathione (GSH) and catalase/superoxide dismutase was unable to prevent enzyme inactivation. Nevertheless, competitive inhibitor fluvoxamine exhibited a concentration-dependent protective effect against the XTT-induced CYP1A2 inactivation. A GSH trapping experiment provided strong evidence for the production of epoxide or/and γ-ketoenal intermediates resulting from the metabolic activation of XTT. Furthermore, pretreatment of rats with XTT was found to significantly increase the C max and area under the curve of plasma tacrine relative to those of tacrine administration alone.

show abstract

Section: ■ Discussionmentioning

confidence: 99%

“…Residual CYP1A2 activity was determined as described above. The partition coefficient of CYP1A2 inactivation by XTT was assessed by the graphs previously described …”

Section: Methodsmentioning

confidence: 99%

Mechanistic Study of Xanthotoxin-Mediated Inactivation of CYP1A2 and Related Drug–Drug Interaction with Tacrine

Ran

Liao

Wang

et al. 2023

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…With this similitude, we would expect notopterol to also be a strong inactivator of cytochrome P450 enzymes, and, indeed, the literature studies show it to be a strong inhibitor of CYP3A4 [24]. Additionally, a very recent article [25] demonstrated that notopterol inhibits around 94% of CYP2D6 activity, followed by CYP2B6 (77%) and CYP3A4 (50%).…”

mentioning

confidence: 87%

The Grapefruit Effect: Interaction between Cytochrome P450 and Coumarin Food Components, Bergamottin, Fraxidin and Osthole. X-ray Crystal Structure and DFT Studies

et al. 2020

View full text Add to dashboard Cite

Coumarins are plant-derived secondary metabolites. The crystal structure of three coumarins—bergamottin, osthole and fraxidin—are described and we analyze intermolecular interactions and their role in crystal formation. Bergamottin is a furanocoumarin found in citrus plants, which is a strong inhibitor of the principal human metabolizing enzyme, cytochrome P450 3A4 (CYP3A4). The crystal structure determinations of three coumarins give us the geometrical parameters and reveal the parallel-displaced π–π stacking and hydrogen bonding intermolecular interactions used for molecular assembly in the crystal structure. A quite strong (less than 3.4 Å) stacking interaction of bergamottin appears to be a determining feature that distinguishes it from other coumarins studied in this work. Our DFT computational studies on the three natural products of the same coumarin family docked into the active site of CYP3A4 (PDB 4D78) show different behavior for these coumarins at the active site. When the substrate is bergamottin, the importance of π-π stacking and hydrogen bonding, which can anchor the substrate in place, appears fundamental. In contrast, fraxidin and osthole show carbonyl coordination to iron. Our docking calculations show that the bergamottin tendency towards π–π stacking is important and likely influences its interactions with the heme group of CYP3A4.

show abstract

“…Mammalian cytochrome P450 (CYPs) enzymes are a superfamily of heme-containing monooxygenase enzymes that play a crucial role in oxidative metabolism of a wide variety of endogenous compounds and xenobiotics, including environmental toxins, therapeutic drugs, and herbal constituents. − In most cases, CYP-catalyzed oxidative reactions lead to the detoxification of xenobiotics, by forming the hydrophilic metabolites that can be readily excreted from the body. However, in a few cases, some agents can be converted by mammalian CYPs to form the reactive intermediate(s) that may covalently bond on the nucleophile groups of a variety of biological macromolecules (such as proteins or DNA) and then induce idiosyncratic hepatotoxicity or mechanism-based inactivation of CYPs. − In the past few decades, a number of structurally diverse compounds have been found to be activated by mammalian CYPs and to trigger idiosyncratic toxicity, − which has aroused widespread concern from both the scientists in pharmaceutical industry and the clinical pharmacists. , …”

Section: Introductionmentioning

confidence: 99%

Unique Oxidative Metabolism of Bufalin Generates Two Reactive Metabolites That Strongly Inactivate Human Cytochrome P450 3A

Ning

Zou

et al. 2022

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Identifying the alert groups of mechanism-based inactivators of human cytochrome P450s (hCYPs) is very helpful for early prediction of drug toxicity and for rational drug design to avoid idiosyncratic toxicity. Here, we report that a natural compound bufalin (BF) could time-dependently inactivate hCYP3A via complex CYP-catalyzed cascade oxidative metabolism. Metabolite profiling and time-dependent inhibition assays showed that 3-keto-bufalin (3-KBF), a unique nonpolar oxidative metabolite of BF, was the key substance responsible for hCYP3A inactivation. Further investigations demonstrated that 3-KBF was further metabolized by hCYPs to generate two mono-hydroxylated metabolites, which could be readily dehydrated and then covalently bound on glutathione or hCYP3A4. Collectively, this study uncovers unique CYP-catalyzed cascade oxidative pathways of BF in which two reactive intermediates bearing a Michael acceptor are finally formed as hCYP3A inactivators. These findings expand the current knowledge of CYP inactivators and suggest that some steroids bearing the 3-keto group may trigger time-dependent CYP3A inactivation.

show abstract

Mechanism-based inactivation of cytochrome P450 2D6 by Notopterol

Cited by 7 publications

References 22 publications

Mechanistic Study of Xanthotoxin-Mediated Inactivation of CYP1A2 and Related Drug–Drug Interaction with Tacrine

Mechanistic Study of Xanthotoxin-Mediated Inactivation of CYP1A2 and Related Drug–Drug Interaction with Tacrine

The Grapefruit Effect: Interaction between Cytochrome P450 and Coumarin Food Components, Bergamottin, Fraxidin and Osthole. X-ray Crystal Structure and DFT Studies

Unique Oxidative Metabolism of Bufalin Generates Two Reactive Metabolites That Strongly Inactivate Human Cytochrome P450 3A

Contact Info

Product

Resources

About