Development and Characterization of MDR1 (<i>Mdr1a/b</i>) CRISPR/Cas9 Knockout Rat Model

Liang, Chenmeizi; Zhao, Junfang; Lu, Jian; Zhang, Yuanjin; Ma, Xinrun; Shang, Xuyang; Li, Yongmei; Ma, Xueyun; Liu, Mingyao; Wang, Xin

doi:10.1124/dmd.118.084277

Cited by 23 publications

(19 citation statements)

References 45 publications

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“…It is interesting that there were no significant compensatory changes in other CYP isoforms in Cyp2b KO mice, which may be due to low CYP2B hepatic expression, especially in male mice 318 . In 2019, a novel MDR1 ( Mdr1a/b ) double-knockout rat model was generated in Sprague Dawley rats by the CRISPR/Cas9 technology 319 . The loss of MDR1 function significantly increased digoxin uptake in Mdr1a/b − / − rats.…”

Section: Novel Animal Models For Dmpk Studiesmentioning

confidence: 99%

Current trends in drug metabolism and pharmacokinetics

Meng

Yang

et al. 2019

Acta Pharmaceutica Sinica B

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188

124

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Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug–drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice.

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Section: Novel Animal Models For Dmpk Studiesmentioning

confidence: 99%

Current trends in drug metabolism and pharmacokinetics

Meng

Yang

et al. 2019

Acta Pharmaceutica Sinica B

Self Cite

188

124

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“…The construction of gene editing rats by CRISPR/Cas9 technology has made great progress in drug metabolism and pharmacokinetics (Lu et al, 2021). For example, we have successfully constructed CYP2E1 (-/-) (Wang et al, 2016), CYP3A1/2 (-/-) (Lu et al, 2017), CYP2J3/10 (-/-) (Lu et al, 2020a), Mdr1a/b (-/-) (Liang et al, 2019), and Slco1b2 (-/-) (Ma et al, 2020) rat models through CRISPR/Cas9, and applied them to the exploration of pharmacokinetics and drug-drug interactions Qin et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Sun

Zhang

et al. 2021

Drug Metab Dispos

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Cytochrome P450 1A2 (CYP1A2) as one of the most important CYP isoforms is involved in the biotransformation of many important endogenous and exogenous substances. CYP1A2 also plays an important role in the development of many diseases because it is involved in the biotransformation of precancerous substances and poisons. Although the generation of Cyp1a2 knockout (KO) mouse model has been reported, there are still no relevant rat models for the study of CYP1A2-mediated pharmacokinetics and diseases. In this report, CYP1A2 KO rat model was established successfully by CRISPR/Cas9 without any detectable off-target effect. Compared with wild-type rats, this model showed a loss of CYP1A2 protein expression in the liver. The results of pharmacokinetics in vivo and incubation in vitro of specific substrates of CYP1A2 confirmed the lack of function of CYP1A2 in KO rats. In further studies of potential compensatory effects, we found that CYP1A1 was significantly up-regulated, and CYP2E1, CYP3A2 and LXRβ were down-regulated in KO rats. In addition, CYP1A2 KO rats exhibited a significant increase in serum cholesterol and free testosterone, accompanied by mild liver damage and lipid deposition, suggesting that CYP1A2 deficiency affects lipid metabolism and liver function to a certain extent. In summary, we successfully constructed the CYP1A2 KO rat model, which provides a useful tool for studying the metabolic function and physiological function of CYP1A2.

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“…This system has been applied to the study of drug metabolism genes, drug transporters, nuclear receptors and ADMET gene regulatory elements 1 . Rat models for DMPK research, generated by using CRISPR-Cas9, are summarized in Table 2 46 , 47 , 48 , 49 , 50 , 51 , 52 .…”

Section: Application Of Crispr-cas9 Technology In Animal Model Generationmentioning

confidence: 99%

“…These models allow the study of the role of specific drug transporters in DMPK research. For example, we generated a novel Abcb1 (Abcb1a/b) double KO rat model by the CRISPR-Cas9 system, which can be used as a powerful tool to study the function of MDR1 in drug absorption, tumor multidrug resistance and drug target validation 51 . In addition, the Slco1b2 KO rat model was also successfully constructed by CRISPR-Cas9 technology 52 .…”

Section: Application Of Crispr-cas9 Technology In Animal Model Generationmentioning

confidence: 99%

CRISPR-Cas9: A method for establishing rat models of drug metabolism and pharmacokinetics

Liu

Guo

et al. 2021

Acta Pharmaceutica Sinica B

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The 2020 Nobel Prize in Chemistry recognized CRISPR-Cas9, a super-selective and precise gene editing tool. CRISPR-Cas9 has an obvious advantage in editing multiple genes in the same cell, and presents great potential in disease treatment and animal model construction. In recent years, CRISPR-Cas9 has been used to establish a series of rat models of drug metabolism and pharmacokinetics (DMPK), such as Cyp , Abcb1 , Oatp1b2 gene knockout rats. These new rat models are not only widely used in the study of drug metabolism, chemical toxicity, and carcinogenicity, but also promote the study of DMPK related mechanism, and further strengthen the relationship between drug metabolism and pharmacology/toxicology. This review systematically introduces the advantages and disadvantages of CRISPR-Cas9, summarizes the methods of establishing DMPK rat models, discusses the main challenges in this field, and proposes strategies to overcome these problems.

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Development and Characterization of MDR1 (Mdr1a/b) CRISPR/Cas9 Knockout Rat Model

Cited by 23 publications

References 45 publications

Current trends in drug metabolism and pharmacokinetics

Current trends in drug metabolism and pharmacokinetics

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

CRISPR-Cas9: A method for establishing rat models of drug metabolism and pharmacokinetics

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