ArticleEndocrinology2014
Mechanism of inhibition of estrogen biosynthesis by azole fungicides.
Article in Endocrinology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 73 citations in OpenAlex.
- Toxicity testing of pesticides in zebrafish-a systematic review on chemicals and associated toxicological endpoints.Environmental science and pollution research international · 2020Pooled it
- "Protective" Imazalil vs Its Negative Effects on Immune System Cells-Neutrophils.Life (Basel, Switzerland) · 2026Article
- Advancements in the nanodelivery of azole-based fungicides to control oil palm pathogenic fungi.Heliyon · 2024Review
- Disease phenotypic screening in neuron-glia cocultures identifies blockers of inflammatory neurodegeneration.iScience · 2024Article
- Article
- Switching from Aromatase Inhibitors to Dual Targeting Flavonoid-Based Compounds for Breast Cancer Treatment.Molecules (Basel, Switzerland) · 2023Article
- Antifungal Drug Plasma Exposures: A Possible Contribution of Vitamin D-Related Gene Variants.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Effects of the administration of miconazole by different routes on the biomarkers of the "steroidal module" of the Athlete Biological Passport.Drug testing and analysis · 2021Article
- Mechanisms of allosteric and mixed mode aromatase inhibitors.RSC chemical biology · 2021Article
- Roles for Structural Biology in the Discovery of Drugs and Agrochemicals Targeting Sterol 14α-Demethylases.Journal of fungi (Basel, Switzerland) · 2021Review
- Strategies to Better Target Fungal Squalene Monooxygenase.Journal of fungi (Basel, Switzerland) · 2021Review
- Azole pharmaceuticals induce germinal vesicle breakdown (GVBD) in preovulatory oocytes of zebrafish (Danio rerio): an in vitro study.Environmental science and pollution research international · 2021Article
- Reconsidering Aromatase for Breast Cancer Treatment: New Roles for an Old Target.Molecules (Basel, Switzerland) · 2020Review
- Targeting Orthosteric and Allosteric Pockets of Aromatase via Dual-Mode Novel Azole Inhibitors.ACS medicinal chemistry letters · 2020Article
- Phosphorylation of human placental aromatase CYP19A1.The Biochemical journal · 2019Article
- Pesticides as the drivers of neuropsychotic diseases, cancers, and teratogenicity among agro-workers as well as general public.Environmental science and pollution research international · 2019Review
- Testosterone complex and non-steroidal ligands of human aromatase.The Journal of steroid biochemistry and molecular biology · 2018Article
- Zebrafish: A Model for the Study of Toxicants Affecting Muscle Development and Function.International journal of molecular sciences · 2016Review
- Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure-Function Perspective.Journal of medicinal chemistry · 2016Review
- The impact of Anastrazole and Letrozole on the metabolic profile in an experimental animal model.Scientific reports · 2015Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Biosynthesis of estrogens from androgens is catalyzed by cytochrome P450 aromatase. Aromatase inhibition by the triazole compounds letrozole (LTZ) and anastrozole is a prevalent therapy for estrogen-dependent postmenopausal breast cancer. Azoles are widely used as agricultural fungicides and antimycotic drugs that target 14α-demethylase. Some were previously shown to inhibit aromatase, thereby raising the possibility of endocrine disruptive effects. However, mechanistic analysis of their inhibition has never been undertaken. We have evaluated the inhibitory effects of 3 common fungicides, bifonazole, imazalil, and flusilazole, in human aromatase purified from placenta and compared them with LTZ, the most potent inhibitor of aromatase. Bifonazole exhibits strong inhibitory effects with an IC50 of 270nM and Ki (Michaeles-Menten inhibition constant) of 68nM, compared with 10nM and 13nM, respectively, for LTZ. The IC50 and Ki are 1100nM and 278nM for imazilil and 3200nM and 547nM for flusilazole, respectively. Analyses of inhibition kinetics suggest that the modes of inhibition by azole fungicides are mixed or competitive, whereas LTZ inhibition could be noncompetitive or mixed. We interpret the inhibition mechanism in the context of the x-ray structure of aromatase-androstenedione complex. Structural data show that aromatase has 3 binding pockets in relation to the heme. The substrate-binding cavity at the heme-distal site closely compliments the structures of the natural substrate, androstenedione, and steroidal aromatase inhibitors. Because the structures of LTZ and the azole fungicides are entirely dissimilar to the androstenedione backbone, the azoles possibly inhibit by binding to a structurally rearranged active site, the 2 other catalytically important sites, or both, in agreement with the kinetics data.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.