Drug-metabolizing enzyme, transporter, and nuclear receptor genetically modified mouse models

Abstract

Determining the in vivo significance of a specific enzyme, transporter, or xenobiotic receptor in drug metabolism and pharmacokinetics may be hampered by gene multiplicity and complexity, levels of expression, and interaction between various components involved. The development of knockout (loss-of-function) and transgenic (gain-of-function) mouse models opens the door to the improved understanding of gene function in a whole-body system. There is also growing interest in the development of humanized mice to overcome species differences in drug metabolism and disposition. This review, therefore, aims to summarize and discuss some successful examples of drug-metabolizing enzyme, transporter, and nuclear-receptor genetically modified mouse models. These genetically modified mouse models have been proven as invaluable models for understanding in vivo function of drug-metabolizing enzymes, transporters, and xenobiotic receptors in drug metabolism and transport, as well as predicting potential drug-drug interaction and toxicity in humans. Nevertheless, concerns remain about interpretation of data obtained from such genetically modified mouse models, in which the expression of related genes is altered significantly.

Figure 1

Studies with wild-type and Tg-CYP2D6 mice revealed a significant (P < 0.05; two-way ANOVA) impact of CYP2D6 status on (a) harmaline pharmacokinetics (5 and 15 mg/kg, i.p.; N = 3 at each time point), and (b) drug effects on mouse marble-burying behavior (0–10 mg/kg, i.p.; N = 14 in each group) (Wu et al., 2009).

Figure 2

Sexual dimorphism and developmental expression of human CYP3A4 transgene, as well as murine P450s. (a) Expression of the CYP3A4 transgene and murine Cyp3a and Cyp2b is dependent on gender and age [2–16 week (W)] in mouse livers (Yu et al., 2005). (b) Hepatic CYP3A4 and murine P450 expression profiles are changed in mice following growth hormone (GH) infusion, compared to the SHAM control (Cheung et al., 2006). HLM, human liver microsomes.

Figure 3

Sharp difference in ivermectin (p.o.) toxicity between Mdr1a-null and wild-type mice (Schinkel et al., 1994).

Figure 4

Differential induction of CYP3A4/Cyp3a by pregnenolone-16α-carbonitrile (PCN) and rifampicin (RIF) in wild-type and PXR-humanized mice (Ma et al., 2007). Mice treated with drug vehicle were used as control (CON).