Modification of single-nucleotide polymorphism in a fully humanized CYP3A mouse by genome editing technology View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-12

AUTHORS

Satoshi Abe, Kaoru Kobayashi, Asami Oji, Tetsushi Sakuma, Kanako Kazuki, Shoko Takehara, Kazuomi Nakamura, Azusa Okada, Yasuko Tsukazaki, Naoto Senda, Kazuhisa Honma, Takashi Yamamoto, Masahito Ikawa, Kan Chiba, Mitsuo Oshimura, Yasuhiro Kazuki

ABSTRACT

Cytochrome P450, family 3, subfamily A (CYP3A) enzymes metabolize approximately 50% of commercially available drugs. Recently, we developed fully humanized transchromosomic (Tc) CYP3A mice with the CYP3A cluster including CYP3A4, CYP3A5, CYP3A7, and CYP3A43. Our humanized CYP3A mice have the CYP3A5*3 (g.6986G) allele, resulting in the almost absence of CYP3A5 protein expression in the liver and intestine. To produce model mice for predicting CYP3A5's contribution to pharmacokinetics, we performed a single-nucleotide polymorphism (SNP) modification of CYP3A5 (g.6986G to A, *3 to *1) on the CYP3A cluster using genome editing in both mouse ES cells and fertilized eggs, and produced humanized CYP3A5*1 mice recapitulating the CYP3A5*1 carrier phenotype in humans. The humanized CYP3A mouse with CYP3A5*1 is the first Tc mouse for predicting the SNP effect on pharmacokinetics in humans. The combination of Tc technology and genome editing enables the production of useful humanized models that reflect humans with different SNPs. More... »

PAGES

15189

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-017-15033-0

DOI

http://dx.doi.org/10.1038/s41598-017-15033-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1092522974

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29123154


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