PMID- 37286362
OWN - NLM
STAT- MEDLINE
DCOM- 20230918
LR  - 20230920
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 51
IP  - 10
DP  - 2023 Oct
TI  - Use of Traditional and Proteomic Methods in the Assessment of a Preclinical Model 
      of Preeclampsia.
PG  - 1308-1315
LID - 10.1124/dmd.122.001080 [doi]
AB  - Recent studies have demonstrated downregulation of breast cancer resistance 
      protein (BCRP/ABCG2) in placenta obtained from women with preeclampsia (PE). BCRP 
      is highly expressed in placenta and plays an important role in preventing 
      xenobiotics from entering the fetal compartment. Although PE is often 
      therapeutically managed with drugs that are substrates of BCRP, there are limited 
      studies on the impact of PE on fetal drug exposure. Due to ethical concerns, use 
      of preclinical models is an important approach. Thus, by using proteomic and 
      traditional methods, we characterized transporter changes in an immunologic rat 
      model of PE to determine its utility and predictive value for future drug 
      disposition studies. PE was induced by daily administration of low-dose endotoxin 
      (0.01-0.04 mg/kg) to rats on gestational days (GD) 13-16, urine was collected, 
      and rats were sacrificed on GD17 or GD18. PE rats shared similar phenotype to PE 
      patients, including proteinuria, and increased levels of tumor necrosis factor alpha 
      and interleukin 6. Transcript and protein levels of Bcrp were significantly 
      downregulated in placenta of PE rats on GD18. multidrug resistance 1a, multidrug 
      resistance 1b, and organic anion transporting polypeptide 2B1 mRNA were also 
      decreased in PE. Proteomics revealed activation of various hallmarks of PE 
      including immune activation, oxidative stress, endoplasmic reticulum stress and 
      apoptosis. Overall, our results demonstrated that the immunologic PE rat model 
      exhibits numerous similarities to human PE along with dysregulation of placental 
      transporters. Therefore, this model may be useful in examining the impact of PE 
      on the maternal and fetal disposition of BCRP substrates. SIGNIFICANCE STATEMENT: 
      Fully characterizing preclinical models of disease is necessary to determine 
      their validity to human conditions. Combining traditional and proteomic methods 
      of model characterization, we identified numerous phenotypic similarities between 
      our model of preeclampsia and human disease. The alignment with human 
      pathophysiological changes allows for more confident use of this preclinical 
      model.
CI  - Copyright (c) 2023 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Dai, Wanying
AU  - Dai W
AD  - Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University 
      of Toronto, Toronto, Canada.
FAU - Pollinzi, Angela
AU  - Pollinzi A
AD  - Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University 
      of Toronto, Toronto, Canada.
FAU - Piquette-Miller, Micheline
AU  - Piquette-Miller M
AD  - Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University 
      of Toronto, Toronto, Canada m.piquette.miller@utoronto.ca.
LA  - eng
GR  - PJT-169195/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230607
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Pharmaceutical Preparations)
SB  - IM
MH  - Pregnancy
MH  - Rats
MH  - Female
MH  - Humans
MH  - Animals
MH  - *Placenta/metabolism
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics/metabolism
MH  - *Pre-Eclampsia/metabolism/pathology
MH  - Proteomics
MH  - ATP-Binding Cassette Transporters/metabolism
MH  - Neoplasm Proteins/metabolism
MH  - Pharmaceutical Preparations/metabolism
EDAT- 2023/06/08 01:08
MHDA- 2023/09/18 12:42
CRDT- 2023/06/07 21:37
PHST- 2022/08/15 00:00 [received]
PHST- 2023/05/24 00:00 [accepted]
PHST- 2023/09/18 12:42 [medline]
PHST- 2023/06/08 01:08 [pubmed]
PHST- 2023/06/07 21:37 [entrez]
AID - dmd.122.001080 [pii]
AID - 10.1124/dmd.122.001080 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2023 Oct;51(10):1308-1315. doi: 10.1124/dmd.122.001080. Epub 
      2023 Jun 7.