title: Assessment of Protein Binding of 5-Hydroxythalidomide Bioactivated in Humanized Mice with Human P450 3A-Chromosome or Hepatocytes by Two-Dimensional Electrophoresis/Accelerator Mass Spectrometry.
abstract: Bioactivation of 5-hydroxy-[carbonyl-(14)C]thalidomide, a known metabolite of thalidomide, by human artificial or native cytochrome P450 3A enzymes, and nonspecific binding in livers of mice was assessed using two-dimensional electrophoresis combined with accelerator mass spectrometry. The apparent major target proteins were liver microsomal cytochrome c oxidase subunit 6B1 and ATP synthase subunit α in mice containing humanized P450 3A genes or transplanted humanized liver. Liver cytosolic retinal dehydrogenase 1 and glutathione transferase A1 were targets in humanized mice with P450 3A and hepatocytes, respectively. 5-Hydroxythalidomide is bioactivated by human P450 3A enzymes and trapped with proteins nonspecifically in humanized mice.
authors.affiliation: Showa Pharmaceutical University , Machida, Tokyo 194-8543, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Central Institute for Experimental Animals , Kawasaki-ku, Kawasaki 210-0821, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.affiliation: Graduate School of Medical Science, Tottori University , Yonago, Tottori 683-8503, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.affiliation: Idea Consultants Inc. , Suminoe-ku, Osaka 559-8519, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Oofusa
authors.affiliation: Otsuka Pharmaceutical Factory, Inc. , Naruto, Tokushima 772-8601, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Kuribayashi
authors.affiliation: Showa Pharmaceutical University , Machida, Tokyo 194-8543, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Sekisui Medical Co. , Chuo-ku, Tokyo 103-0027, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ninomiya
authors.affiliation: Drug Discovery and Development Institute , Tsukuba, Ibaragi 305-0036, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Horie
authors.affiliation: Graduate School of Engineering, Nagoya Institute of Technology , Showa-ku, Nagoya 466-8555, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Shibata
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-0146, United States.
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015180:Electrophoresis, Gel, Two-Dimensional; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D051379:Mice; D011485:Protein Binding; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C544471:5-hydroxythalidomide; D013792:Thalidomide; D003577:Cytochrome P-450 Enzyme System