Expression of CYP450 enzymes in human fetal membranes and its implications in xenobiotic metabolism during pregnancy.
Cytochrome P450
Drug metabolism
Fetal membrane
Pharmacokinetics
Placenta
Pregnancy
Toxicant metabolism
Journal
Life sciences
ISSN: 1879-0631
Titre abrégé: Life Sci
Pays: Netherlands
ID NLM: 0375521
Informations de publication
Date de publication:
15 Oct 2022
15 Oct 2022
Historique:
received:
20
06
2022
revised:
26
07
2022
accepted:
03
08
2022
pubmed:
9
8
2022
medline:
13
10
2022
entrez:
8
8
2022
Statut:
ppublish
Résumé
Environmental exposure to toxicants is a major risk factor for spontaneous preterm birth (PTB, <37 weeks). Toxicants and drugs administered to patients are metabolized primarily by the cytochrome P450 (CYP450) system. Along with the adult and fetal liver, the placenta, a critical feto-maternal interface organ, expresses CYP450 enzymes that metabolize these xenobiotics. However, the contribution of the fetal membranes, another tissue of the feto-maternal interface, to the expression of CYP450 enzymes and the detoxification of xenobiotics remains unknown. This study characterized CYP450 expression and determined the functional activity of CYP450 enzymes in fetal membranes. RNA sequencing (RNA-Seq) of placental and fetal membrane tissues and cells was done. Differential expressions of CYP450 genes were compared and validated via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) between the two tissues. The functional activity of major CYP450 enzymes was determined using a fluorophore-based enzymatic assay in the presence and absence of their corresponding inhibitors. With the exception of genes that regulate cholesterol metabolism, the expression profile of CYP450 genes was similar between placental and fetal membranes tissues/cells. RT-qPCR analysis confirmed these findings with significant levels of mRNA for major CYP450 genes being detectable in amnion epithelial cells (AECs) and chorion trophoblasts cells (CTCs). Biochemical analyses revealed significant CYP450 enzymatic activities that were sensitive to specific inhibitors for both AECs and CTCs, suggesting that the genes were expressed as functional enzymes. This is the first study to determine global expression of CYP450 enzymes in fetal membranes which may play a role in xenobiotic metabolism during pregnancy. Given that many women are exposed to environmental toxins or require medications during pregnancy, a better understanding of their role in metabolism is required to develop safer therapeutics and prevent adverse outcomes.
Sections du résumé
BACKGROUND
BACKGROUND
Environmental exposure to toxicants is a major risk factor for spontaneous preterm birth (PTB, <37 weeks). Toxicants and drugs administered to patients are metabolized primarily by the cytochrome P450 (CYP450) system. Along with the adult and fetal liver, the placenta, a critical feto-maternal interface organ, expresses CYP450 enzymes that metabolize these xenobiotics. However, the contribution of the fetal membranes, another tissue of the feto-maternal interface, to the expression of CYP450 enzymes and the detoxification of xenobiotics remains unknown.
AIMS
OBJECTIVE
This study characterized CYP450 expression and determined the functional activity of CYP450 enzymes in fetal membranes.
MAIN METHODS
METHODS
RNA sequencing (RNA-Seq) of placental and fetal membrane tissues and cells was done. Differential expressions of CYP450 genes were compared and validated via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) between the two tissues. The functional activity of major CYP450 enzymes was determined using a fluorophore-based enzymatic assay in the presence and absence of their corresponding inhibitors.
KEY FINDINGS
RESULTS
With the exception of genes that regulate cholesterol metabolism, the expression profile of CYP450 genes was similar between placental and fetal membranes tissues/cells. RT-qPCR analysis confirmed these findings with significant levels of mRNA for major CYP450 genes being detectable in amnion epithelial cells (AECs) and chorion trophoblasts cells (CTCs). Biochemical analyses revealed significant CYP450 enzymatic activities that were sensitive to specific inhibitors for both AECs and CTCs, suggesting that the genes were expressed as functional enzymes.
SIGNIFICANCE
CONCLUSIONS
This is the first study to determine global expression of CYP450 enzymes in fetal membranes which may play a role in xenobiotic metabolism during pregnancy. Given that many women are exposed to environmental toxins or require medications during pregnancy, a better understanding of their role in metabolism is required to develop safer therapeutics and prevent adverse outcomes.
Identifiants
pubmed: 35940219
pii: S0024-3205(22)00567-7
doi: 10.1016/j.lfs.2022.120867
pii:
doi:
Substances chimiques
RNA, Messenger
0
Xenobiotics
0
Cytochrome P-450 Enzyme System
9035-51-2
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
120867Subventions
Organisme : NICHD NIH HHS
ID : R01 HD100729
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.