Cargando…
Determining the IC(50) Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver
Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [(11)C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liv...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655258/ https://www.ncbi.nlm.nih.gov/pubmed/26635974 http://dx.doi.org/10.1155/2015/321820 |
_version_ | 1782402159034236928 |
---|---|
author | Raymond, Lendelle Rayani, Nikita Polson, Grace Sikorski, Kylie Lian, Ailin VanAlstine-Parris, Melissa A. |
author_facet | Raymond, Lendelle Rayani, Nikita Polson, Grace Sikorski, Kylie Lian, Ailin VanAlstine-Parris, Melissa A. |
author_sort | Raymond, Lendelle |
collection | PubMed |
description | Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [(11)C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC(50) = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC(50) = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC(50) = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [(11)C]-vorozole is binding to in the liver. |
format | Online Article Text |
id | pubmed-4655258 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-46552582015-12-03 Determining the IC(50) Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver Raymond, Lendelle Rayani, Nikita Polson, Grace Sikorski, Kylie Lian, Ailin VanAlstine-Parris, Melissa A. Enzyme Res Research Article Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [(11)C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC(50) = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC(50) = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC(50) = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [(11)C]-vorozole is binding to in the liver. Hindawi Publishing Corporation 2015 2015-11-09 /pmc/articles/PMC4655258/ /pubmed/26635974 http://dx.doi.org/10.1155/2015/321820 Text en Copyright © 2015 Lendelle Raymond et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Raymond, Lendelle Rayani, Nikita Polson, Grace Sikorski, Kylie Lian, Ailin VanAlstine-Parris, Melissa A. Determining the IC(50) Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver |
title | Determining the IC(50) Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver |
title_full | Determining the IC(50) Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver |
title_fullStr | Determining the IC(50) Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver |
title_full_unstemmed | Determining the IC(50) Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver |
title_short | Determining the IC(50) Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver |
title_sort | determining the ic(50) values for vorozole and letrozole, on a series of human liver cytochrome p450s, to help determine the binding site of vorozole in the liver |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655258/ https://www.ncbi.nlm.nih.gov/pubmed/26635974 http://dx.doi.org/10.1155/2015/321820 |
work_keys_str_mv | AT raymondlendelle determiningtheic50valuesforvorozoleandletrozoleonaseriesofhumanlivercytochromep450stohelpdeterminethebindingsiteofvorozoleintheliver AT rayaninikita determiningtheic50valuesforvorozoleandletrozoleonaseriesofhumanlivercytochromep450stohelpdeterminethebindingsiteofvorozoleintheliver AT polsongrace determiningtheic50valuesforvorozoleandletrozoleonaseriesofhumanlivercytochromep450stohelpdeterminethebindingsiteofvorozoleintheliver AT sikorskikylie determiningtheic50valuesforvorozoleandletrozoleonaseriesofhumanlivercytochromep450stohelpdeterminethebindingsiteofvorozoleintheliver AT lianailin determiningtheic50valuesforvorozoleandletrozoleonaseriesofhumanlivercytochromep450stohelpdeterminethebindingsiteofvorozoleintheliver AT vanalstineparrismelissaa determiningtheic50valuesforvorozoleandletrozoleonaseriesofhumanlivercytochromep450stohelpdeterminethebindingsiteofvorozoleintheliver |