title: Thalidomide-induced limb abnormalities in a humanized CYP3A mouse model.
abstract: Thalidomide is a teratogen in humans but not in rodents. It causes multiple birth defects including malformations of limbs, ears, and other organs. However, the species-specific mechanism of thalidomide teratogenicity is not completely understood. Reproduction of the human teratogenicity of thalidomide in rodents has previously failed because of the lack of a model reflecting human drug metabolism. In addition, because the maternal metabolic effect cannot be eliminated, the migration of unchanged thalidomide to embryos is suppressed, and the metabolic activation is insufficient to develop teratogenicity. Previously, we generated transchromosomic mice containing a human cytochrome P450 (CYP) 3A cluster in which the endogenous mouse Cyp3a genes were deleted. Here, we determined whether human CYP3A or mouse Cyp3a enzyme expression was related to the species difference in a whole embryo culture system using humanized CYP3A mouse embryos. Thalidomide-treated embryos with the human CYP3A gene cluster showed limb abnormalities, and human CYP3A was expressed in the placenta, suggesting that human CYP3A in the placenta may contribute to the teratogenicity of thalidomide. These data suggest that the humanized CYP3A mouse is a useful model to predict embryonic toxicity in humans.
authors.affiliation: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.|Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.affiliation: Faculty of Family and Consumer Sciences, Department of Nutrition and Dietetics, Kamakura Women's University, 6-1-3 Ofuna, Kamakura, Kanagawa 247-8512, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akita
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.|Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Osaki
authors.affiliation: Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Satoh
authors.affiliation: Division of Toxicology, Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ohta
authors.affiliation: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Abe
authors.affiliation: Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Takehara
authors.affiliation: Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Kazuki
authors.affiliation: Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University, Nishi 6, Kita 12, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kamataki
authors.affiliation: Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000473:pathology*; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000187:drug effects*; D005121:Extremities; D005260:Female; D015870:Gene Expression; D006801:Humans; D008658:Inactivation, Metabolic; D051379:Mice; D008822:Mice, Transgenic; D010920:Placenta / Q000187:drug effects* / Q000201:enzymology; D011247:Pregnancy; D013045:Species Specificity; D013723:Teratogens / Q000633:toxicity*; D013792:Thalidomide / Q000633:toxicity*; D019076:Transgenes; D008565:Membrane Proteins
chemical_list: D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D013723:Teratogens; D013792:Thalidomide; C104464:CYP3A protein, human; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins