PXD024158-1

PXD024158 is an original dataset announced via ProteomeXchange.

Title	Hepatic cytochrome P450 abundance and activity in the developing and adult Göttingen Minipig: pivotal data for PBPK modeling
Description	The Göttingen Minipig is gaining ground as nonrodent species in safety testing of drugs for pediatric indications. Due to developmental changes in pharmacokinetics (PK) and pharmacodynamics (PD), physiologically-based pharmacokinetic (PBPK) models are built to better predict drug exposure in children and to aid species selection for nonclinical safety studies. These PBPK models require high quality physiological and PK/PD data such as protein abundance of drug metabolizing enzymes. These data are available for man and rat, but scarce for the Göttingen Minipig. The aim of this study was to assess hepatic cytochrome P450 (CYP) protein abundance in the developing Göttingen Minipig by using mass spectrometry. In addition, sex-related differences in CYP protein abundance and correlation of CYP enzyme activity with CYP protein abundance were assessed. The following age groups were included: gestational day (GD) 84 - 86 (n = 8), GD 108 (n = 6), postnatal day (PND) 1 (n = 8), PND 3 (n = 8), PND 7 (n = 8), PND 28 (n = 8) and adult (n = 8). Liver microsomes were extracted and protein abundance was compared to that in adult animals. Next, the CYP protein abundance was correlated to CYP enzyme activity in the same biological samples. In general, CYP protein abundance gradually increased during development. However, we observed a stable protein expression over time for CYP4A24 and CYP20A1 and for CYP51A1, a high protein expression during the fetal stages was followed by a decrease during the first month of life and an increase towards adulthood. Sex-related differences were observed for CYP4V2_2a and CYP20A1 at PND 1 with highest expression in females for both isoforms. In the adult samples, sex-related differences were detected for CYP1A1, CYP1A2, CYP2A19, CYP2E1_2, CYP3A22, CYP4V2_2a and CYP4V2_2b with higher values in female compared to male Göttingen Minipigs. The correlation analysis between CYP protein abundance and CYP enzyme activity showed that CYP3A22 protein abundance correlated clearly with the metabolism of midazolam at PND 7. These data are remarkably comparable to human data and provide a valuable step forward in the construction of a neonatal and juvenile Göttingen Minipig PBPK model.
HostingRepository	PRIDE
AnnounceDate	2021-02-26
AnnouncementXML	Submission_2021-02-26_09:04:26.051.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Laura Buyssens
SpeciesList	scientific name: Sus scrofa domesticus (domestic pig); NCBI TaxID: 9825;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2021-02-12 05:39:26	ID requested
⏵ 1	2021-02-26 09:04:26	announced

Dataset with its publication pending

submitter keyword: CYP, protein abundance, ontogeny, Göttingen Minipig, pediatrics, mass spectrometry

Steven Jan Van Cruchten
contact affiliation	Comparative Perinatal Development - Department of Veterinary Sciences - Faculty of Pharmaceutical, Biomedical and Veterinary Sciences - University of Antwerp
contact email	steven.vancruchten@uantwerpen.be
lab head
Laura Buyssens
contact affiliation	University of Antwerp
contact email	laura.buyssens@uantwerpen.be
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024158
     1. Label: PRIDE project
     2. Name: Hepatic cytochrome P450 abundance and activity in the developing and adult Göttingen Minipig: pivotal data for PBPK modeling