Format

Send to

Choose Destination
Toxicology. 2018 Jul 1;404-405:76-85. doi: 10.1016/j.tox.2018.06.001. Epub 2018 Jun 4.

Liver lobe and strain differences in the activity of murine cytochrome P450 enzymes.

Author information

1
German Federal Institute for Risk Assessment, German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Str. 8-10, 10589 Berlin, Germany. Electronic address: juliane.rudeck@bfr.bund.de.
2
German Federal Institute for Risk Assessment, German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Str. 8-10, 10589 Berlin, Germany. Electronic address: bettina.bert@bfr.bund.de.
3
German Federal Institute for Risk Assessment, German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Str. 8-10, 10589 Berlin, Germany. Electronic address: philip.marx-stoelting@bfr.bund.de.
4
German Federal Institute for Risk Assessment, German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Str. 8-10, 10589 Berlin, Germany; Charité - Universitätsmedizin Berlin, Cooperate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Clinical Pharmacology and Toxicology, Charitéplatz 1, 10117 Berlin, Germany. Electronic address: gilbert.schoenfelder@bfr.bund.de.
5
German Federal Institute for Risk Assessment, German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Str. 8-10, 10589 Berlin, Germany. Electronic address: silvia.vogl@bfr.bund.de.

Abstract

The cytochrome P450 (CYP) enzyme superfamily is the most important enzyme system for phase I biotransformation. For toxico- and pharmacokinetic studies, use of liver-based microsomes, including those of mice, is state-of-the-art to study CYP-dependent metabolism. However, reproducibility and interpretation of these data is still very variable, partly because current testing guidelines do not cover details on organ sampling and potential liver lobe differences. Hence, we analyzed CYP activity, CYP protein content, mRNA expression of CYP1A, CYP2C, CYP2D and CYP3A isozymes, and cytochrome P450 reductase (CPR) activity of the four different liver lobes and processus papillaris of male C57BL/6J mice in comparison to whole liver. Additionally, we used whole liver of Balb/cJ and 129S1/SvImJ for strain comparison. Our data show significant differences in CYP activity, being most prominent in lobus sinister lateralis and lobus medialis, and lowest in processus papillaris. These differences were not caused by varying Cyp gene expression or CYP protein level, but partly correspond with lobe specific CPR activities. We also observed significant strain differences in CYP mRNA expression and activities with overall high activities in 129S1/SvImJ mice and low activities in Balb/cJ mice compared to C57BL/6J mice. In addition, strain specific differences in CYP2C and CYP2D activity seem to be reflected in strain dependent differences in CPR activity. In summary, our results indicate that in mice CYP activity and gene expression are strain dependent and may vary highly between liver lobes. To ensure reproducibility and comparability of different probes and studies, this should be taken into account when liver samples are collected for the analysis of CYP-dependent metabolism.

KEYWORDS:

Cytochrome P450; Liver lobe differences; Liver microsomes; Mouse

PMID:
29879457
DOI:
10.1016/j.tox.2018.06.001
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center