scholarly journals Towards an Understanding of the Mode of Action of Human Aromatase Activity for Azoles through Quantum Chemical Descriptors-Based Regression and Structure Activity Relationship Modeling Analysis

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 739
Author(s):  
Chayawan Chayawan ◽  
Cosimo Toma ◽  
Emilio Benfenati ◽  
Ana Y. Caballero Alfonso
Keyword(s):  
Endocrine System ◽  
Spherical Shape ◽  
Aromatase Activity ◽  
Quantum Chemical Descriptors ◽  
Multilinear Regression ◽  
Chemical Safety ◽  
Antagonist Activity ◽  
Binding Behavior ◽  
Modeling Analysis ◽  
Human Aromatase

Aromatase is an enzyme member of the cytochrome P450 superfamily coded by the CYP19A1 gene. Its main action is the conversion of androgens into estrogens, transforming androstenedione into estrone and testosterone into estradiol. This enzyme is present in several tissues and it has a key role in the maintenance of the balance of androgens and estrogens, and therefore in the regulation of the endocrine system. With regard to chemical safety and human health, azoles, which are used as agrochemicals and pharmaceuticals, are potential endocrine disruptors due to their agonist or antagonist interactions with the human aromatase enzyme. This theoretical study investigated the active agonist and antagonist properties of “chemical classes of azoles” to determine the relationships of azole interaction with CYP19A1, using stereochemical and electronic properties of the molecules through classification and multilinear regression (MLR) modeling. The antagonist activities for the same substituent on diazoles and triazoles vary with its chemical composition and its position and both heterocyclic systems require aromatic substituents. The triazoles require the spherical shape and diazoles have to be in proper proportion of the branching index and the number of ring systems for the inhibition. Considering the electronic aspects, triazole antagonist activity depends on the electrophilicity index that originates from interelectronic exchange interaction (ωHF) and the LUMO energy ( E LUMO PM 7 ), and the diazole antagonist activity originates from the penultimate orbital ( E HOMONL PM 7 ) of diazoles. The regression models for agonist activity show that it is opposed by the static charges but favored by the delocalized charges on the diazoles and thiazoles. This study proposes that the electron penetration of azoles toward heme group decides the binding behavior and stereochemistry requirement for antagonist activity against CYP19A1 enzyme.

Inhibitory effect of Rhus verniciflua Stokes extract on human aromatase activity; butin is its major bioactive component

2014 ◽  
Vol 24 (7) ◽  
pp. 1730-1733 ◽  
Author(s):  
Myeong Hyeon Park ◽  
In Sook Kim ◽  
Sun-A Kim ◽  
Chun-Soo Na ◽  
Cheol Yi Hong ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Aromatase Activity ◽  
Bioactive Component ◽  
Rhus Verniciflua Stokes ◽  
Rhus Verniciflua ◽  
Human Aromatase

Effects of endocrine active substances in wildlife species: Genetic, biochemical, and physiological factors in variable susceptibility to endocrine disruptors

2003 ◽  
Vol 75 (11-12) ◽  
pp. 2335-2341 ◽  
Author(s):  
Shin'ichiro Kawai ◽  
M. Kobayashi ◽  
Hideo Kaneko
Keyword(s):  
Endocrine System ◽  
Aquatic Organisms ◽  
Xenobiotic Metabolism ◽  
Environmental Chemicals ◽  
Ah Receptor ◽  
Blood Levels ◽  
Aromatase Activity ◽  
Physiological Factors ◽  
Wildlife Species ◽  
Active Substances

Responses to endocrine active substances (EASs) in animals are various, and differences between the responses among individuals, populations and species are well known. These differences are observed not only in EASs but in most environmental chemicals including synthetic and naturally occurring ones. The basic differences in sensitivity to EASs are attributed to that of affinity or specificity of the receptors to EASs at the cellular level. Although the nucleotide sequences encoding for estrogen receptor proteins have been documented in several species and the functions of the receptors are the same, the ability to bind the natural hormones and the estrogenic xenobiotics is not necessarily identical. The reproductive endocrine system is basically common among vertebrates, but chemical types of hormones, physiological roles of hormones and the basal blood levels of hormones differ among each species, especially in sex steroids. These differences cause various types of responses and sensitivity to EASs among animal species. Xenobiotic metabolism is important for the genetical, biochemical and physiological factors concerning the influence of EASs. Some EASs directly inhibit cytochrome P450 (CYP) activity as was reported in tributyltin that inhibits CYP19 (aromatase) activity causing imposex in neogastropods. Some organochlorines including dioxins stimulate aryl hydrocarbon (Ah) receptor-mediated xenobiotic metabolism, and result in the metabolic disruption of steroid hormones such as estrogen as were reported in eggshell thinning in birds of prey and uterus occlusion in seals. CYP activity greatly differs among wildlife species in both terrestrial and aquatic organisms, and these differences are significantly responsible for the multiple effects or toxicity of EASs. Sex and age differences also cause different responses to EASs and are largely due to the differences in xenobiotic metabolizing activities.

scholarly journals Effect of sildenafil on human aromatase activity: From in vitro structural analysis to catalysis and inhibition in cells

2017 ◽  
Vol 165 ◽  
pp. 438-447 ◽  
Author(s):  
Roberta Baravalle ◽  
Francesca Valetti ◽  
Gianluca Catucci ◽  
Giovanna Gambarotta ◽  
Mario Chiesa ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Aromatase Activity ◽  
Human Aromatase ◽  
In Cells

Effects of Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) Hull Extracts on the Secretion of Progesterone and Estradiol In Vivo and In Vitro

2007 ◽  
Vol 232 (9) ◽  
pp. 1181-1194 ◽  
Author(s):  
Shih-Min Hsia ◽  
Chih-Lan Yeh ◽  
Yueh-Hsiung Kuo ◽  
Paulus S. Wang ◽  
Wenchang Chiang
Keyword(s):  
Ethyl Acetate ◽  
Enzyme Activities ◽  
Regulatory Protein ◽  
Endocrine System ◽  
Female Rats ◽  
Aromatase Activity ◽  
Water Fraction ◽  
Protein Expressions

Adlay ( Coix lachryma-jobi L. var. ma-yuen Stapf.) has been used as a traditional Chinese medicine for dysfunction of the endocrine system. However, there have been few studies on the effects of adlay seed on the endocrine system. In the present study, both the in vivo and in vitro effects of methanolic extracts of adlay hull (AHM) on progesterone synthesis were studied. AHM was partitioned with four different solvents: water, 1-butanol, ethyl acetate, and n-hexane. Four fractions, namely, AHM-Wa (water fraction), AHM-Bu (1-butanol fraction), AHM-EA (ethyl acetate fraction), and AHM-Hex ( n-hexane fraction), were respectively obtained. Granulosa cells (GCs) were prepared from pregnant mare serum gonadotropin-primed immature female rats and were challenged with different reagents, including human chorionic gonadotropin (hCG; 0.5 IU/ml), 8-bromo-adenosine-3′,5′-cyclic monophosphate (8-Br-cAMP; 0.1 m M), forskolin (10 μ M), 25-OH-cholesterol (10 μ M), and pregnenolone (10 μ M), in the presence or absence of AHM (100 μg/ml). The functions of steroidogenic enzymes, including protein expression of the steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage enzyme (P450scc), protein kinase A (PKA), and aromatase activity, were investigated. The expression of StAR mRNA was also explored by using real-time reverse transcription–polymerase chain reaction. In the in vivo study, AHM decreased plasma progesterone and estradiol levels after an intravenous injection of AHM (2 mg/ ml/kg). In the in vitro studies, AHM decreased progesterone and estradiol via inhibition of (i) the cAMP-PKA signal transduction pathway, (ii) cAMP accumulation, (iii) P450scc and 3β-HSD enzyme activities, (iv) PKA, P450scc and StAR protein expressions and StAR mRNA expression, and (v) aromatase activity in rat GCs. These results suggest that AHM decreased the production of progesterone via mechanisms involving the inhibition of the cAMP pathway, enzyme activities, and the protein expressions of P450scc and StAR in rat GCs.

scholarly journals EPIDEMIOLOGICAL, TOXICOLOGICAL AND MOLEСULAR-GENETIC ASPECTS OF ENDOCRINE DISRUPTING CHEMICALS IN THE CHEMICAL SAFETY PROBLEM

2018 ◽  
Vol 97 (3) ◽  
pp. 197-203
Author(s):  
Oksana O. Sinitsyna ◽  
Yu. A. Rakhmanin ◽  
Z. I. Zholdakova ◽  
M. G. Aksenova ◽  
A. V. Kirillov ◽  
...  
Keyword(s):  
Chemical Structure ◽  
Endocrine Disrupting Chemicals ◽  
Endocrine System ◽  
Structural Features ◽  
The Body ◽  
Target Cells ◽  
Chemical Safety ◽  
Endocrine Disrupting ◽  
The Impact

The literature review has shown the problem of endocrine disrupting chemicals (EDC) to be associated with their wide distribution in the environment, the abundance, and variety of the chemical structure. Three leading mechanisms of EDCs action are identified as follows: imitation of the naturally occurring hormones action, blocking of receptors within the target cells of hormones, the impact of their kinetics in the body. Epidemiological studies indicate an increase in diseases caused by a disorder of the hormonal system. They are associated with the effect of EDCs. Substances that are completely dissimilar in chemical structure can cause the same effects. According to WHO [6], it is impossible, based on the chemical structure, to determine whether a substance is a disruptor of the endocrine system. However, some structural features determine the estrogenic, thyreogenic and glucocorticoid activity of chemicals. Hence, the need to differentiate the specific (primary) effect of a chemical substance on the endocrine system and the indirect (secondary) effect on it via other mechanisms comes to the fore. In own research, specific mechanisms were shown to be determined in the experiment when studying the complexity of effects, taking into account the processes of adaptation and decompensation, and identifying the effects manifested with the lowest doses. One of the methodological approaches can be the developed “structure-biotransformation-activity” prediction system aimed at revealing the primary types of effects: using quantum-chemical calculations and the plausible reasoning class (called the JSM-reasoning in honour of John Stuart Mill) logico-combinatorial method, it was possible to identify structural fragments of substances responsible for the manifestation of carcinogenic, allergenic effects, methemoglobin formation, etc. The results of clinical studies show the use of pharmacological drugs as models for in vivo study of the effects of EDC to allow not only studying atypical mechanisms of the impact of EDCs from the point of view of molecular genetics but also to predict the individual susceptibility to them taking into account polymorphism of candidate genes. The EDCs problem poses the need for a complex of interdisciplinary research, including three main relationships: exposure assessment-biomonitoring data-the prevalence of endocrine-dependent diseases, taking into account the qualitative and quantitative contribution of individual endocrine disrupters to the development of an ecologically dependent endocrine pathology using molecular genetic methods.

scholarly journals Safeguarding Female Reproductive Health Against Endocrine Disrupting Chemicals—The FREIA Project

2020 ◽  
Vol 21 (9) ◽  
pp. 3215
Author(s):  
Majorie B. M. van Duursen ◽  
Julie Boberg ◽  
Sofie Christiansen ◽  
Lisa Connolly ◽  
Pauliina Damdimopoulou ◽  
...  
Keyword(s):  
Reproductive Health ◽  
Endocrine Disrupting Chemicals ◽  
Endocrine System ◽  
Test Methods ◽  
Incidence Rates ◽  
Chemical Safety ◽  
Embryonic And Fetal Development ◽  
Female Reproductive Health ◽  
Endocrine Disrupting ◽  
And Function

Currently available test methods are not well-suited for the identification of chemicals that disturb hormonal processes involved in female reproductive development and function. This renders women’s reproductive health at increasing risk globally, which, coupled with increasing incidence rates of reproductive disorders, is of great concern. A woman’s reproductive health is largely established during embryonic and fetal development and subsequently matures during puberty. The endocrine system influences development, maturation, and function of the female reproductive system, thereby making appropriate hormone levels imperative for correct functioning of reproductive processes. It is concerning that the effects of human-made chemicals on the endocrine system and female reproductive health are poorly addressed in regulatory chemical safety assessment, partly because adequate test methods are lacking. Our EU-funded project FREIA aims to address this need by increasing understanding of how endocrine disrupting chemicals (EDCs) can impact female reproductive health. We will use this information to provide better test methods that enable fit-for-purpose chemical regulation and then share our knowledge, promote a sustainable society, and improve the reproductive health of women globally.

scholarly journals Polymorphism on human aromatase affects protein dynamics and substrate binding: spectroscopic evidence

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Giovanna Di Nardo ◽  
Almerinda Di Venere ◽  
Chao Zhang ◽  
Eleonora Nicolai ◽  
Silvia Castrignanò ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ligand Binding ◽  
Exchange Rates ◽  
Protein Dynamics ◽  
Substrate Binding ◽  
Single Amino Acid ◽  
Aromatase Activity ◽  
Wild Type ◽  
Ligand Free ◽  
Human Aromatase

AbstractHuman aromatase is a member of the cytochrome P450 superfamily, involved in steroid hormones biosynthesis. In particular, it converts androgen into estrogens being therefore responsible for the correct sex steroids balance. Due to its capacity in producing estrogens it has also been considered as a promising target for breast cancer therapy. Two single-nucleotide polymorphisms (R264C and R264H) have been shown to alter aromatase activity and they have been associated to an increased or decreased risk for estrogen-dependent pathologies. Here, the effect of these mutations on the protein dynamics is investigated by UV/FTIR and time resolved fluorescence spectroscopy. H/D exchange rates were measured by FTIR for the three proteins in the ligand-free, substrate- and inhibitor-bound forms and the data indicate that the wild-type enzyme undergoes a conformational change leading to a more compact tertiary structure upon substrate or inhibitor binding. Indeed, the H/D exchange rates are decreased when a ligand is present. In the variants, the exchange rates in the ligand-free and –bound forms are similar, indicating that a structural change is lacking, despite the single amino acid substitution is located in the peripheral shell of the protein molecule. Moreover, the fluorescence lifetimes data show that the quenching effect on tryptophan-224 observed upon ligand binding in the wild-type, is absent in both variants. Since this residue is located in the catalytic pocket, these findings suggest that substrate entrance and/or retention in the active site is partially compromised in both mutants. A contact network analysis demonstrates that the protein structure is organized in two main clusters, whose connectivity is altered by ligand binding, especially in correspondence of helix-G, where the amino acid substitutions occur. Our findings demonstrate that SNPs resulting in mutations on aromatase surface modify the protein flexibility that is required for substrate binding and catalysis. The cluster analysis provides a rationale for such effect, suggesting helix G as a possible target for aromatase inhibition.

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