3D Spheroid Primary Human Hepatocytes for Prediction of Cytochrome P450 and Drug Transporter Induction.
Humans
Cytochrome P-450 CYP2C8
/ metabolism
Cytochrome P-450 CYP2C19
/ metabolism
Cytochrome P-450 CYP3A
/ metabolism
Cytochrome P-450 CYP2B6
/ metabolism
Rifampin
/ pharmacology
Cytochrome P-450 CYP2D6
/ metabolism
Cytochrome P-450 CYP2C9
/ metabolism
Cells, Cultured
Cytochrome P-450 Enzyme System
/ genetics
Hepatocytes
/ metabolism
Membrane Transport Proteins
/ genetics
Carrier Proteins
/ metabolism
RNA, Messenger
/ metabolism
Liver-Specific Organic Anion Transporter 1
/ metabolism
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
04
11
2022
accepted:
04
03
2023
medline:
22
5
2023
pubmed:
13
3
2023
entrez:
12
3
2023
Statut:
ppublish
Résumé
Primary human hepatocytes (PHHs) have been the gold standard in vitro model for the human liver and are crucial to predict hepatic drug-drug interactions. The aim of this work was to assess the utility of 3D spheroid PHHs to study induction of important cytochrome P450 (CYP) enzymes and drug transporters. The 3D spheroid PHHs from three different donors were treated for 4 days with rifampicin, dicloxacillin, flucloxacillin, phenobarbital, carbamazepine, efavirenz, omeprazole, or β-naphthoflavone. Induction of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and transporters P-glycoprotein (P-gp)/ABCB1, multidrug resistance-associated protein 2 (MRP2)/ABCC2, ABCG2, organic cation transporter 1 (OCT1)/SLC22A1, SLC22A7, SLCO1B1, and SLCO1B3 were evaluated at mRNA and protein levels. Enzyme activity of CYP3A4, CYP2B6, CYP2C19, and CYP2D6 were also assessed. Induction of CYP3A4 protein and mRNA correlated well for all donors and compounds and had a maximal induction of five- to sixfold for rifampicin, which closely correlates to induction observed in clinical studies. Rifampicin induced the mRNA of CYP2B6 and CYP2C8 by 9- and 12-fold, whereas the protein levels of these CYPs reached 2- and 3-fold induction, respectively. Rifampicin induced CYP2C9 protein by 1.4-fold, whereas the induction of CYP2C9 mRNA was over 2-fold in all donors. Rifampicin induced ABCB1, ABCC2, and ABCG2 by 2-fold. In conclusion, 3D spheroid PHHs is a valid model to investigate mRNA and protein induction of hepatic drug-metabolizing enzymes and transporters, and this model provides a solid basis to study induction of CYPs and transporters, which translates to clinical relevance.
Substances chimiques
Cytochrome P-450 CYP2C8
EC 1.14.14.1
Cytochrome P-450 CYP2C19
EC 1.14.14.1
Cytochrome P-450 CYP3A
EC 1.14.14.1
Cytochrome P-450 CYP2B6
EC 1.14.14.1
Rifampin
VJT6J7R4TR
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Cytochrome P-450 CYP2C9
EC 1.14.13.-
Cytochrome P-450 Enzyme System
9035-51-2
Membrane Transport Proteins
0
Carrier Proteins
0
RNA, Messenger
0
SLCO1B1 protein, human
0
Liver-Specific Organic Anion Transporter 1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1284-1294Informations de copyright
© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
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