Is the unique benzodiazepine structure interacting with CYP enzymes to affect steroid synthesis in vitro?

Research output: Contribution to journalJournal articlepeer-review

Standard

Is the unique benzodiazepine structure interacting with CYP enzymes to affect steroid synthesis in vitro? / Johannsen, Malene Louise; Munkboel, Cecilie Hurup; Jorgensen, Flemming Steen; Styrishave, Bjarne.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 205, 105765, 2021.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Johannsen, ML, Munkboel, CH, Jorgensen, FS & Styrishave, B 2021, 'Is the unique benzodiazepine structure interacting with CYP enzymes to affect steroid synthesis in vitro?', Journal of Steroid Biochemistry and Molecular Biology, vol. 205, 105765. https://doi.org/10.1016/j.jsbmb.2020.105765

APA

Johannsen, M. L., Munkboel, C. H., Jorgensen, F. S., & Styrishave, B. (2021). Is the unique benzodiazepine structure interacting with CYP enzymes to affect steroid synthesis in vitro? Journal of Steroid Biochemistry and Molecular Biology, 205, [105765]. https://doi.org/10.1016/j.jsbmb.2020.105765

Vancouver

Johannsen ML, Munkboel CH, Jorgensen FS, Styrishave B. Is the unique benzodiazepine structure interacting with CYP enzymes to affect steroid synthesis in vitro? Journal of Steroid Biochemistry and Molecular Biology. 2021;205. 105765. https://doi.org/10.1016/j.jsbmb.2020.105765

Author

Johannsen, Malene Louise ; Munkboel, Cecilie Hurup ; Jorgensen, Flemming Steen ; Styrishave, Bjarne. / Is the unique benzodiazepine structure interacting with CYP enzymes to affect steroid synthesis in vitro?. In: Journal of Steroid Biochemistry and Molecular Biology. 2021 ; Vol. 205.

Bibtex

@article{6f409e6c0a504193b73daee7fdd9abad,
title = "Is the unique benzodiazepine structure interacting with CYP enzymes to affect steroid synthesis in vitro?",
abstract = "The aim of this project was to investigate the endocrine disrupting effects of three gamma-aminobutyric acid type A receptor (GABA(A)R) agonists, diazepam (DZ), oxazepam (OX) and alprazolam (AL) using the steroidogenic in vitro H295R cell line assay, a recombinant CYP17A1 assay, qPCR analysis and computational modelling. Similar effects for DZ and OX on the steroidogenesis were observed in the H295R experiment at therapeutically relevant concentrations. Progestagens and corticosteroids were increased up to 10 fold and androgens were decreased indicating CYP17A1 lyase inhibition. For DZ the inhibition on both the hydroxylase and lyase was confirmed by the recombinant CYP17A1 assay, whereas OX did not appear to directly affect the recombinant CYP17A1 enzyme. Androgens were decreased when exposing the H295R cells to AL, indicating a CYP17A1 lyase inhibition. However, this was not confirmed by the recombinant CYP17A1 assay but a down-regulation in gene expression was observed for StAR and CYP17A1. The present study showed that the three investigated benzodiazepines (BZDs) are rather potent endocrine disruptors in vitro, exerting endocrine effects close the therapeutic C-max. Both direct and indirect effects on steroidogenesis were observed, but molecular modelling indicated no direct interactions between the heme group in the steroidogenic CYP enzymes and the unique diazepin structure. In contrast, physicochemical properties such as high log P, structure and molecular weight similar to that of steroids appeared to influence the endocrine disrupting abilities of the investigated pharmaceuticals in vitro. Docking of the three BZDs in CYP17A1 and CYP21A2 confirmed that shape complementarity and hydrophobic effects seem to determine the binding modes.",
keywords = "Diazepam, Oxazepam, Alprazolam, H295R, Endocrine disruption, Steroidogenesis in silico modelling, Docking, Binding mode",
author = "Johannsen, {Malene Louise} and Munkboel, {Cecilie Hurup} and Jorgensen, {Flemming Steen} and Bjarne Styrishave",
year = "2021",
doi = "10.1016/j.jsbmb.2020.105765",
language = "English",
volume = "205",
journal = "Journal of Steroid Biochemistry and Molecular Biology",
issn = "0960-0760",
publisher = "Pergamon Press",

}

RIS

TY - JOUR

T1 - Is the unique benzodiazepine structure interacting with CYP enzymes to affect steroid synthesis in vitro?

AU - Johannsen, Malene Louise

AU - Munkboel, Cecilie Hurup

AU - Jorgensen, Flemming Steen

AU - Styrishave, Bjarne

PY - 2021

Y1 - 2021

N2 - The aim of this project was to investigate the endocrine disrupting effects of three gamma-aminobutyric acid type A receptor (GABA(A)R) agonists, diazepam (DZ), oxazepam (OX) and alprazolam (AL) using the steroidogenic in vitro H295R cell line assay, a recombinant CYP17A1 assay, qPCR analysis and computational modelling. Similar effects for DZ and OX on the steroidogenesis were observed in the H295R experiment at therapeutically relevant concentrations. Progestagens and corticosteroids were increased up to 10 fold and androgens were decreased indicating CYP17A1 lyase inhibition. For DZ the inhibition on both the hydroxylase and lyase was confirmed by the recombinant CYP17A1 assay, whereas OX did not appear to directly affect the recombinant CYP17A1 enzyme. Androgens were decreased when exposing the H295R cells to AL, indicating a CYP17A1 lyase inhibition. However, this was not confirmed by the recombinant CYP17A1 assay but a down-regulation in gene expression was observed for StAR and CYP17A1. The present study showed that the three investigated benzodiazepines (BZDs) are rather potent endocrine disruptors in vitro, exerting endocrine effects close the therapeutic C-max. Both direct and indirect effects on steroidogenesis were observed, but molecular modelling indicated no direct interactions between the heme group in the steroidogenic CYP enzymes and the unique diazepin structure. In contrast, physicochemical properties such as high log P, structure and molecular weight similar to that of steroids appeared to influence the endocrine disrupting abilities of the investigated pharmaceuticals in vitro. Docking of the three BZDs in CYP17A1 and CYP21A2 confirmed that shape complementarity and hydrophobic effects seem to determine the binding modes.

AB - The aim of this project was to investigate the endocrine disrupting effects of three gamma-aminobutyric acid type A receptor (GABA(A)R) agonists, diazepam (DZ), oxazepam (OX) and alprazolam (AL) using the steroidogenic in vitro H295R cell line assay, a recombinant CYP17A1 assay, qPCR analysis and computational modelling. Similar effects for DZ and OX on the steroidogenesis were observed in the H295R experiment at therapeutically relevant concentrations. Progestagens and corticosteroids were increased up to 10 fold and androgens were decreased indicating CYP17A1 lyase inhibition. For DZ the inhibition on both the hydroxylase and lyase was confirmed by the recombinant CYP17A1 assay, whereas OX did not appear to directly affect the recombinant CYP17A1 enzyme. Androgens were decreased when exposing the H295R cells to AL, indicating a CYP17A1 lyase inhibition. However, this was not confirmed by the recombinant CYP17A1 assay but a down-regulation in gene expression was observed for StAR and CYP17A1. The present study showed that the three investigated benzodiazepines (BZDs) are rather potent endocrine disruptors in vitro, exerting endocrine effects close the therapeutic C-max. Both direct and indirect effects on steroidogenesis were observed, but molecular modelling indicated no direct interactions between the heme group in the steroidogenic CYP enzymes and the unique diazepin structure. In contrast, physicochemical properties such as high log P, structure and molecular weight similar to that of steroids appeared to influence the endocrine disrupting abilities of the investigated pharmaceuticals in vitro. Docking of the three BZDs in CYP17A1 and CYP21A2 confirmed that shape complementarity and hydrophobic effects seem to determine the binding modes.

KW - Diazepam

KW - Oxazepam

KW - Alprazolam

KW - H295R

KW - Endocrine disruption

KW - Steroidogenesis in silico modelling

KW - Docking

KW - Binding mode

U2 - 10.1016/j.jsbmb.2020.105765

DO - 10.1016/j.jsbmb.2020.105765

M3 - Journal article

C2 - 32991989

VL - 205

JO - Journal of Steroid Biochemistry and Molecular Biology

JF - Journal of Steroid Biochemistry and Molecular Biology

SN - 0960-0760

M1 - 105765

ER -

ID: 255781747