Trans-chromosomic mice containing a human CYP3A cluster for prediction of xenobiotic metabolism in humans

Yasuhiro Kazuki, Kaoru Kobayashi, Sasitorn Aueviriyavit, Takeshi Oshima, Yoshimi Kuroiwa, Yasuko Tsukazaki, Naoto Senda, Hiroki Kawakami, Sumio Ohtsuki, Satoshi Abe, Masato Takiguchi, Hidetoshi Hoshiya, Naoyo Kajitani, Shoko Takehara, Kinya Kubo, Tetsuya Terasaki, Kan Chiba, Kazuma Tomizuka, Mitsuo Oshimura

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)

Abstract

Human CYP3A is the most abundant P450 isozyme present in the human liver and small intestine, and metabolizes around 50% of medical drugs on the market. The human CYP3A subfamily comprises four members (CYP3A4, CYP3A5, CYP3A7, CYP3A43) encoded on human chromosome 7. However, transgenic mouse lines carrying the entire human CYP3A cluster have not been constructed because of limitations in conventional cloning techniques. Here, we show that the introduction of a human artificial chromosome (HAC) containing the entire genomic human CYP3A locus recapitulates tissue- and stage-specific expression of human CYP3A genes and xenobiotic metabolism in mice. About 700 kb of the entire CYP3A genomic segment was cloned into a HAC (CYP3A-HAC), and trans-chromosomic (Tc) mice carrying a single copy of germline-transmittable CYP3A-HAC were generated via a chromosome-engineering technique. The tissue- and stage-specific expression profiles of CYP3A genes were consistent with those seen in humans. We further generated mice carrying the CYP3A-HAC in the background homozygous for targeted deletion of most endogenous Cyp3a genes. In this mouse strain with 'fully humanized' CYP3A genes, the kinetics of triazolam metabolism, CYP3A-mediated mechanism-based inactivation effects and formation of fetal-specific metabolites of dehydroepiandrosterone observed in humans were well reproduced. Thus, these mice are likely to be valuable in evaluating novel drugs metabolized by CYP3A enzymes and in studying the regulation of human CYP3A gene expression. Furthermore, this system can also be used for generating Tc mice carrying other human metabolic genes.

Original languageEnglish
Article numberdds468
Pages (from-to)578-592
Number of pages15
JournalHuman molecular genetics
Volume22
Issue number3
DOIs
Publication statusPublished - 2013 Feb

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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