Development of humanized steroid and xenobiotic receptor mouse by homologous knock-in of the human steroid and xenobiotic receptor ligand binding domain sequence

Igarashi, Katsuhide; Kitajima, Satoshi; Aisaki, Ken Ichi; Tanemura, Kentaro; Taquahashi, Yuhji; Moriyama, Noriko; Ikeno, Eriko; Matsuda, Nae; Saga, Yumiko; Blumberg, Bruce; Kanno, Jun

doi:10.2131/jts.37.373

Cited by 25 publications

(23 citation statements)

References 19 publications

(17 reference statements)

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“…The advantage of mouse over rats are two fold: the smaller amount of test chemicals and laboratory space needed and the possibility to use transgenic and/or knockout mice, such as AhR/Cyp1a1 knock out and humanized mice, such as for cytochrome P450 (Scheer et al, 2008) and for steroid and xenobiotic receptor (Igarashi et al, 2012) for further mechanistic studies including that of U-shaped dose response.…”

Section: Discussionmentioning

confidence: 99%

Ovariectomized mouse uterotrophic assay of 36 chemicals

Ohta

Takagi²,

Ohmukai

et al. 2012

J. Toxicol. Sci.

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Section: Discussionmentioning

confidence: 99%

Ovariectomized mouse uterotrophic assay of 36 chemicals

Ohta

Takagi²,

Ohmukai

et al. 2012

J. Toxicol. Sci.

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“…For example, peroxisome proliferator-activated receptor (PPAR)α-(25), PPARδ- (12), and steroid and xenobiotic receptor-humanized mice (13) have been produced and used. Our results highlight the need to pay attention to species-specific differences in the efficacy of compounds and the importance of using humanized animal models in drug development.…”

Section: Discussionmentioning

confidence: 99%

Species-specific differences in agonistic activity of ago-allosteric modulators toward glucagon-like peptide 2 receptor

et al. 2012

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“…Subsequently, a double‐transgenic mouse model expressing both hPXR and human cytochrome P450 3A4 ( CYP3A4 ) was generated that displayed robust CYP3A4 induction by rifampicin . The most recent humanized PXR mouse model was generated by expressing a chimeric PXR (mDBD‐hLBD), which was envisioned as minimizing differences in the DNA‐binding affinities of different species. Humanized PXR models provide valuable in vivo information and have widespread applications in the development of PXR modulators.…”

Section: Current Status Of Pxr Antagonist Development Challenges Anmentioning

confidence: 99%

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

Chai

Wright

Chen

2019

Medicinal Research Reviews

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Pregnane X receptor (PXR) is a ligand-activated nuclear receptor (NR) that was originally identified as a master regulator of xenobiotic detoxification. It regulates the expression of drug-metabolizing enzymes and transporters to control the degradation and excretion of endobiotics and xenobiotics, including therapeutic agents. The metabolism and disposition of drugs might compromise their efficacy and possibly cause drug toxicity and/or drug resistance. Because many drugs can promiscuously bind and activate PXR, PXR antagonists might have therapeutic value in preventing and overcoming drug-induced PXR-mediated drug toxicity and drug resistance. Furthermore, PXR is now known to have broader cellular functions, including the regulation of cell proliferation, and glucose and lipid metabolism. Thus, PXR might be involved in human diseases such as cancer and metabolic diseases. The importance of PXR antagonists is discussed in the context of the role of PXR in xenobiotic sensing and other disease-related pathways. This review focuses on the development of PXRantagonists, which has been hampered by the promiscuity of PXR ligand binding. However, substantial progress has been made in recent years, suggesting that it is feasible to develop selective PXR antagonists. We discuss the current status, challenges, and strategies in developing selective PXR antagonists. The strategies are based on the molecular mechanisms of antagonism in related NRs that can be applied to the design of PXR antagonists, primarily driven by structural information.The nuclear receptor (NR) pregnane X receptor (PXR, NR1I2) plays a prominent role in the detoxification system that humans and other organisms utilize to eliminate endobiotics such as steroid hormones, bile acids, and glucose and xenobiotics such as therapeutic agents. Upon the binding of a ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and transporters, leading to the metabolism and, ultimately, clearance of endobiotics and xenobiotics. These chemicals undergo biotransformation and disposition through a series of processes comprising oxidation and conjugation reactions (involving cytochrome P450 enzymes [CYPs], such as CYP3A4, UDP-glucuronosyltransferases, and glutathione-S-transferases, sulfotransferases) and active efflux (involving the transporter proteins multidrug resistance proteins and multidrug resistance-associated proteins). [1][2][3][4] PXR and the detoxification system represent a double-edged sword: Although detoxification serves as a beneficial protection mechanism against toxic compounds, it also compromises therapeutic outcomes by decreasing drug efficacy and possibly inducing drug toxicity and resistance. Therefore, a balance between PXR transcriptional activation and repression is needed, not only to maintain appropriate physiologic levels of endogenous chemicals but also to achieve optimal therapeutic efficacy with fewer drug-induced toxicities. Because of its important role in regulating drug efficacy and drug toxicity, as wel...

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Development of humanized steroid and xenobiotic receptor mouse by homologous knock-in of the human steroid and xenobiotic receptor ligand binding domain sequence

Cited by 25 publications

References 19 publications

Ovariectomized mouse uterotrophic assay of 36 chemicals

Ovariectomized mouse uterotrophic assay of 36 chemicals

Species-specific differences in agonistic activity of ago-allosteric modulators toward glucagon-like peptide 2 receptor

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

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