Non-target biotransformation enzymes as a target for triazole-zinc mixtures
Language English Country Ireland Media print-electronic
Document type Journal Article
PubMed
37422065
DOI
10.1016/j.cbi.2023.110625
PII: S0009-2797(23)00292-2
Knihovny.cz E-resources
- Keywords
- Antifungals, CYP19A1, CYP3A4, Cocktail effect, Inhibitory effect,
- MeSH
- Biotransformation MeSH
- Cytochrome P-450 CYP3A * metabolism MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- Triazoles pharmacology metabolism MeSH
- Zinc * MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Cytochrome P-450 CYP3A * MeSH
- Cytochrome P-450 Enzyme System MeSH
- Triazoles MeSH
- Zinc * MeSH
Triazoles inhibit lanosterol 14α-demethylase and block ergosterol biosynthesis in fungal pathogens. However, they also interact with other cytochrome P450 enzymes and influence non-target metabolic pathways. Disturbingly, triazoles may interact with essential elements. The interaction of penconazole (Pen), cyproconazole (Cyp) and tebuconazole (Teb) with Zn2+ results in the formation of deprotonated ligands in their complexes or in the creation of complexes with Cl- as a counterion or doubly charged complexes. Triazoles, as well as their equimolar cocktails with Zn2+ (10-6 mol/L), decreased the activities of the non-target enzymes CYP19A1 and CYP3A4. Pen most decreased CYP19A1 activity and was best bound to its active centre to block the catalytic cycle in computational analysis. For CYP3A4, Teb was found to be the most effective inhibitor by both, activity assay and interaction with the active centre. Teb/Cyp/Zn2+ and Teb/Pen/Cyp/Zn2+ cocktails also decreased the CYP19A1 activity, which was in correlation with the formation of numerous triazole-Zn2+ complexes.
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