Cargando…

Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368

DN203368 ((E)-3-[1-(4-[4-isopropylpiperazine-1-yl]phenyl) 3-methyl-2-phenylbut-1-en-1-yl] phenol) is a 4-hydroxy tamoxifen analog that is a dual inverse agonist of estrogen-related receptor β/γ (ERRβ/γ). ERRγ is an orphan nuclear receptor that plays an important role in development and homeostasis a...

Descripción completa

Detalles Bibliográficos
Autores principales: Kim, Sin-Eun, Ji, Seung-Bae, Kim, Euihyeon, Jeong, Minseon, Kim, Jina, Lee, Gyung-Min, Seo, Hyung-Ju, Bae, Subin, Jeong, Yeojin, Lee, Sangkyu, Kim, Sunghwan, Lee, Taeho, Cho, Sung Jin, Liu, Kwang-Hyeon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230175/
https://www.ncbi.nlm.nih.gov/pubmed/34072800
http://dx.doi.org/10.3390/pharmaceutics13060776
_version_ 1783713146402242560
author Kim, Sin-Eun
Ji, Seung-Bae
Kim, Euihyeon
Jeong, Minseon
Kim, Jina
Lee, Gyung-Min
Seo, Hyung-Ju
Bae, Subin
Jeong, Yeojin
Lee, Sangkyu
Kim, Sunghwan
Lee, Taeho
Cho, Sung Jin
Liu, Kwang-Hyeon
author_facet Kim, Sin-Eun
Ji, Seung-Bae
Kim, Euihyeon
Jeong, Minseon
Kim, Jina
Lee, Gyung-Min
Seo, Hyung-Ju
Bae, Subin
Jeong, Yeojin
Lee, Sangkyu
Kim, Sunghwan
Lee, Taeho
Cho, Sung Jin
Liu, Kwang-Hyeon
author_sort Kim, Sin-Eun
collection PubMed
description DN203368 ((E)-3-[1-(4-[4-isopropylpiperazine-1-yl]phenyl) 3-methyl-2-phenylbut-1-en-1-yl] phenol) is a 4-hydroxy tamoxifen analog that is a dual inverse agonist of estrogen-related receptor β/γ (ERRβ/γ). ERRγ is an orphan nuclear receptor that plays an important role in development and homeostasis and holds potential as a novel therapeutic target in metabolic diseases such as diabetes mellitus, obesity, and cancer. ERRβ is also one of the orphan nuclear receptors critical for many biological processes, such as development. We investigated the in vitro metabolism of DN203368 by conventional and metabolomic approaches using high-resolution mass spectrometry. The compound (100 μM) was incubated with rat and human liver microsomes in the presence of NADPH. In the metabolomic approach, the m/z value and retention time information obtained from the sample and heat-inactivated control group were statistically evaluated using principal component analysis and orthogonal partial least-squares discriminant analysis. Significant features responsible for group separation were then identified using tandem mass spectra. Seven metabolites of DN203368 were identified in rat liver microsomes and the metabolic pathways include hydroxylation (M1-3), N-oxidation (M4), N-deisopropylation (M5), N,N-dealkylation (M6), and oxidation and dehydrogenation (M7). Only five metabolites (M2, M3, and M5-M7) were detected in human liver microsomes. In the conventional approach using extracted ion monitoring for values of mass increase or decrease by known metabolic reactions, only five metabolites (M1-M5) were found in rat liver microsomes, whereas three metabolites (M2, M3, and M5) were found in human liver microsomes. This study revealed that nontargeted metabolomics combined with high-resolution mass spectrometry and multivariate analysis could be a more efficient tool for drug metabolite identification than the conventional approach. These results might also be useful for understanding the pharmacokinetics and metabolism of DN203368 in animals and humans.
format Online
Article
Text
id pubmed-8230175
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-82301752021-06-26 Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368 Kim, Sin-Eun Ji, Seung-Bae Kim, Euihyeon Jeong, Minseon Kim, Jina Lee, Gyung-Min Seo, Hyung-Ju Bae, Subin Jeong, Yeojin Lee, Sangkyu Kim, Sunghwan Lee, Taeho Cho, Sung Jin Liu, Kwang-Hyeon Pharmaceutics Article DN203368 ((E)-3-[1-(4-[4-isopropylpiperazine-1-yl]phenyl) 3-methyl-2-phenylbut-1-en-1-yl] phenol) is a 4-hydroxy tamoxifen analog that is a dual inverse agonist of estrogen-related receptor β/γ (ERRβ/γ). ERRγ is an orphan nuclear receptor that plays an important role in development and homeostasis and holds potential as a novel therapeutic target in metabolic diseases such as diabetes mellitus, obesity, and cancer. ERRβ is also one of the orphan nuclear receptors critical for many biological processes, such as development. We investigated the in vitro metabolism of DN203368 by conventional and metabolomic approaches using high-resolution mass spectrometry. The compound (100 μM) was incubated with rat and human liver microsomes in the presence of NADPH. In the metabolomic approach, the m/z value and retention time information obtained from the sample and heat-inactivated control group were statistically evaluated using principal component analysis and orthogonal partial least-squares discriminant analysis. Significant features responsible for group separation were then identified using tandem mass spectra. Seven metabolites of DN203368 were identified in rat liver microsomes and the metabolic pathways include hydroxylation (M1-3), N-oxidation (M4), N-deisopropylation (M5), N,N-dealkylation (M6), and oxidation and dehydrogenation (M7). Only five metabolites (M2, M3, and M5-M7) were detected in human liver microsomes. In the conventional approach using extracted ion monitoring for values of mass increase or decrease by known metabolic reactions, only five metabolites (M1-M5) were found in rat liver microsomes, whereas three metabolites (M2, M3, and M5) were found in human liver microsomes. This study revealed that nontargeted metabolomics combined with high-resolution mass spectrometry and multivariate analysis could be a more efficient tool for drug metabolite identification than the conventional approach. These results might also be useful for understanding the pharmacokinetics and metabolism of DN203368 in animals and humans. MDPI 2021-05-31 /pmc/articles/PMC8230175/ /pubmed/34072800 http://dx.doi.org/10.3390/pharmaceutics13060776 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kim, Sin-Eun
Ji, Seung-Bae
Kim, Euihyeon
Jeong, Minseon
Kim, Jina
Lee, Gyung-Min
Seo, Hyung-Ju
Bae, Subin
Jeong, Yeojin
Lee, Sangkyu
Kim, Sunghwan
Lee, Taeho
Cho, Sung Jin
Liu, Kwang-Hyeon
Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368
title Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368
title_full Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368
title_fullStr Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368
title_full_unstemmed Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368
title_short Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368
title_sort nontargeted metabolomics by high-resolution mass spectrometry to study the in vitro metabolism of a dual inverse agonist of estrogen-related receptors β and γ, dn203368
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230175/
https://www.ncbi.nlm.nih.gov/pubmed/34072800
http://dx.doi.org/10.3390/pharmaceutics13060776
work_keys_str_mv AT kimsineun nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT jiseungbae nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT kimeuihyeon nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT jeongminseon nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT kimjina nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT leegyungmin nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT seohyungju nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT baesubin nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT jeongyeojin nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT leesangkyu nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT kimsunghwan nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT leetaeho nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT chosungjin nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368
AT liukwanghyeon nontargetedmetabolomicsbyhighresolutionmassspectrometrytostudytheinvitrometabolismofadualinverseagonistofestrogenrelatedreceptorsbandgdn203368