Cytochrome P450 and Xenobiotic Receptor Humanized Mice

Abstract

Most xenobiotics that enter the body are subjected to metabolism that functions primarily to facilitate their elimination. Metabolism of certain xenobiotics can also result in the production of electrophilic derivatives that can cause cell toxicity and transformation. Many xenobiotics can also activate receptors that in turn induce the expression of genes encoding xenobiotic-metabolizing enzymes and xenobiotic transporters. However, there are marked species differences in the way mammals respond to xenobiotics, which are due in large part to molecular differences in receptors and xenobioticmetabolizing enzymes. This presents a problem in extrapolating data obtained with rodent model systems to humans. There are also polymorphisms in xenobiotic-metabolizing enzymes that can impact drug therapy and cancer susceptibility. In an effort to generate more reliable in vivo systems to study and predict human response to xenobiotics, humanized mice are under development.

Humanized SFTPA1 and SFTPA2 Transgenic Mice Reveal Functional Divergence of SP-A1 and SP-A2

“…Foreign gene expression in transgenic mice is influenced by several factors, including 1) the type of promoter in the construct utilized, 5Ј-UTR, and 3Ј-UTR sequences; 2) the integration position of the transgenic DNA in the transgenic mouse; and 3) the number of copies of the transgene integrated in the genome (44,45). In the present study, as well as in other studies, the use of the 3.7-kb human SP-C promoter sequence ensured alveolar type II cell-specific expression in lung (4, 50 -53, 56).…”

“…Humanized mouse techniques have provided a powerful tool in the study of many human biological processes and in the preclinical testing (44,45). Humanized mice include two types of mice: 1) immunodeficient mice engrafted with human hematopoietic cells and tissues and 2) mice that transgenically express human gene(s) (i.e.…”

Murine Models to Evaluate Novel and Conventional Therapeutic Strategies for Cancer

“…54 Such GEMs are used to study species-associated differences in phenotypes, including responses to drugs or tumor antigens (Ags). 55 Models to study drug responses include GEM mice expressing human cytochrome p450 genes 54 that allow the in vivo analysis of cytochrome P450 metabolism of endogenous and exogenous chemicals, including xenobiotics. One example of these studies is the analysis of cytochrome P450 2E1 (CYP2E1) expression on cisplatin-induced hepatotoxicity, using mice with induced or steady-state CYP2E1 levels and a comparison to knockout and CYP2E1-humanized mice.…”

LC-MS-Based Metabolomics in Drug Metabolism

“…drug metabolism pathways in vivo. Several major XMEs have their corresponding knockouts (including CYP1A1, CYP1A2, CYP1B1, and CYP2E1) and humanized (including CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP2E1, and CYP3A4) mouse lines established (Gonzalez, 2003;Gonzalez, 2004;Gonzalez and Yu, 2006). Gene knockout models are suitable for studying the endogenous function of XMEs as well as their role in xenobiotic metabolism, while humanized models are ideal for studying the underlying mechanisms of interspecies differences in xenobiotic metabolism or using as surrogate models for predicting xenobiotic metabolism in humans.…”

“…Furthermore, a mouse model with all P450 activities abolished by conditional knockout of cytochrome P450 reductase has been established, which can be used to determine whether P450s have any role in the metabolism of individual xenobiotic (Henderson et al, 2003). As for studying the influence of drug-drug interaction on xenobiotic metabolism, knockout and humanized mouse models of several important nuclear receptors (including AhR, PXR, CAR) have also been established (Gonzalez and Yu, 2006). Recently, chimeric mice with liver comprised of more than 80% human hepatocytes have been generated, which further expand the available tools to simulate human-specific xenobiotic metabolism in animal models (Tateno et al, 2004;Katoh and Yokoi, 2007).…”