CYP3A4 Induction in the Liver and Intestine of Pregnane X Receptor/CYP3A-Humanized Mice: Approaches by Mass Spectrometry Imaging and Portal Blood Analysis

• DOI: 10.1124/mol.119.117333
• Publication Date: 2019-08-28T02:15:12Z
• Authors: Kaoru Kobayashi; Jiro Kuze; Satoshi Abe; Shoko Takehara; Genki Minegishi; Katsuhide Igarashi; Satoshi Kitajima; Jun Kanno; Takushi Yamamoto; Mitsuo Oshimura; Yasuhiro Kazuki
• Keywords: Pregnane X receptor; CYP3A

Induction of cytochrome P450 enzyme 3A (CYP3A) in response to pregnane X receptor (PXR) activators shows species-specific differences. To study the induction human CYP3A PXR activators, we generated a double-humanized mouse model and CYP3A. CYP3A-humanized mice by using artificial chromosome (MAC) vector containing entire genomic locus (hCYP3A-MAC line) were bred with PXR-humanized which ligand-binding domain was replaced that PXR, resulting (hCYP3A-MAC/hPXR line). Oral administration activator rifampicin increased hepatic expression CYP3A4 mRNA triazolam (TRZ) 1′- 4-hydroxylation activities, probe liver intestine microsomes hCYP3A-MAC/hPXR mice. The plasma concentration TRZ after oral dosing significantly decreased treatment but not hCYP3A-MAC In addition, mass spectrometry imaging analysis showed formation hydroxy TRZ. 4-hydroxy portal blood also These results suggest line may be useful predict PXR-dependent metabolism substrates intestine. <h3>SIGNIFICANCE STATEMENT</h3> We for PXR. Briefly, Expression triazolam, typical substrate, CYP3A/PXR-humanized enhanced rifampicin, activator. Enhancement firstly shown combination sliced liquid chromatography tandem metabolite triazolam.