Cargando…

Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study.

Flavone and isoflavone phytoestrogens are plant chemicals and are known to be competitive inhibitors of cytochrome P450 aromatase with respect to the androgen substrate. Aromatase is the enzyme that converts androgen to estrogen; therefore, these plant chemicals are thought to be capable of modifyin...

Descripción completa

Detalles Bibliográficos
Autores principales: Kao, Y C, Zhou, C, Sherman, M, Laughton, C A, Chen, S
Formato: Texto
Lenguaje:English
Publicado: 1998
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1533021/
https://www.ncbi.nlm.nih.gov/pubmed/9435150
_version_ 1782128965897420800
author Kao, Y C
Zhou, C
Sherman, M
Laughton, C A
Chen, S
author_facet Kao, Y C
Zhou, C
Sherman, M
Laughton, C A
Chen, S
author_sort Kao, Y C
collection PubMed
description Flavone and isoflavone phytoestrogens are plant chemicals and are known to be competitive inhibitors of cytochrome P450 aromatase with respect to the androgen substrate. Aromatase is the enzyme that converts androgen to estrogen; therefore, these plant chemicals are thought to be capable of modifying the estrogen level in women. In this study, the inhibition profiles of four flavones [chrysin (5, 7-dihydroxyflavone), 7,8-dihydroxyflavone, baicalein (5,6,7-trihydroxyflavone), and galangin (3,5,7-trihydroxyflavone)], two isoflavones [genistein (4,5,7-trihydroxyisoflavone) and biochanin A (5,7-dihydroxy-4-methoxyisoflavone)], one flavanone [naringenin (4, 5,7-trihydroxyflavanone)], and one naphthoflavone (alpha-naphthoflavone) on the wild-type and six human aromatase mutants (I133Y, P308F, D309A, T310S, I395F, and I474Y) were determined. In combination with computer modeling, the binding characteristics and the structure requirement for flavone and isoflavone phytoestrogens to inhibit human aromatase were obtained. These compounds were found to bind to the active site of aromatase in an orientation in which rings A and C mimic rings D and C of the androgen substrate, respectively. This study also provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones.
format Text
id pubmed-1533021
institution National Center for Biotechnology Information
language English
publishDate 1998
record_format MEDLINE/PubMed
spelling pubmed-15330212006-08-08 Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study. Kao, Y C Zhou, C Sherman, M Laughton, C A Chen, S Environ Health Perspect Research Article Flavone and isoflavone phytoestrogens are plant chemicals and are known to be competitive inhibitors of cytochrome P450 aromatase with respect to the androgen substrate. Aromatase is the enzyme that converts androgen to estrogen; therefore, these plant chemicals are thought to be capable of modifying the estrogen level in women. In this study, the inhibition profiles of four flavones [chrysin (5, 7-dihydroxyflavone), 7,8-dihydroxyflavone, baicalein (5,6,7-trihydroxyflavone), and galangin (3,5,7-trihydroxyflavone)], two isoflavones [genistein (4,5,7-trihydroxyisoflavone) and biochanin A (5,7-dihydroxy-4-methoxyisoflavone)], one flavanone [naringenin (4, 5,7-trihydroxyflavanone)], and one naphthoflavone (alpha-naphthoflavone) on the wild-type and six human aromatase mutants (I133Y, P308F, D309A, T310S, I395F, and I474Y) were determined. In combination with computer modeling, the binding characteristics and the structure requirement for flavone and isoflavone phytoestrogens to inhibit human aromatase were obtained. These compounds were found to bind to the active site of aromatase in an orientation in which rings A and C mimic rings D and C of the androgen substrate, respectively. This study also provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones. 1998-02 /pmc/articles/PMC1533021/ /pubmed/9435150 Text en
spellingShingle Research Article
Kao, Y C
Zhou, C
Sherman, M
Laughton, C A
Chen, S
Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study.
title Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study.
title_full Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study.
title_fullStr Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study.
title_full_unstemmed Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study.
title_short Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study.
title_sort molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: a site-directed mutagenesis study.
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1533021/
https://www.ncbi.nlm.nih.gov/pubmed/9435150
work_keys_str_mv AT kaoyc molecularbasisoftheinhibitionofhumanaromataseestrogensynthetasebyflavoneandisoflavonephytoestrogensasitedirectedmutagenesisstudy
AT zhouc molecularbasisoftheinhibitionofhumanaromataseestrogensynthetasebyflavoneandisoflavonephytoestrogensasitedirectedmutagenesisstudy
AT shermanm molecularbasisoftheinhibitionofhumanaromataseestrogensynthetasebyflavoneandisoflavonephytoestrogensasitedirectedmutagenesisstudy
AT laughtonca molecularbasisoftheinhibitionofhumanaromataseestrogensynthetasebyflavoneandisoflavonephytoestrogensasitedirectedmutagenesisstudy
AT chens molecularbasisoftheinhibitionofhumanaromataseestrogensynthetasebyflavoneandisoflavonephytoestrogensasitedirectedmutagenesisstudy