IN VIVO INDUCTION OF HUMAN CYTOCHROME P450 ENZYMES EXPRESSED IN CHIMERIC MICE WITH HUMANIZED LIVER

• Published in: Drug metabolism and disposition Vol. 33; no. 6; pp. 754 - 763
• Main Authors: KATOH, Miki, MATSUI, Tomohito, NAKAJIMA, Miki, TATENO, Chise, SOENO, Yoshinori, HORIE, Toru, IWASAKI, Kazuhide, YOSHIZATO, Katsutoshi, YOKOI, Tsuyoshi
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.06.2005
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Benz(a)Anthracenes - pharmacology; Biological and medical sciences; Child; Chimera - genetics; Chimera - metabolism; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - genetics; Enzyme Induction - drug effects; Enzyme Induction - physiology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; Humans; Infant; Insecta; Isoenzymes - antagonists & inhibitors; Isoenzymes - biosynthesis; Isoenzymes - genetics; Liver - drug effects; Liver - metabolism; Male; Methylcholanthrene; Mice; Mice, SCID; Mice, Transgenic; Oxidoreductases; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - biosynthesis; Recombinant Proteins - genetics; Human; Digestive system; Enzyme; Induction; Cytochrome P450; Liver; Rodentia; In vivo; Vertebrata; Mammalia; Mouse; Animal; Chimera
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.104.002600

The induction and inhibition of human cytochrome P450 (P450) enzymes are clinically responsible for drug interactions. Although the induction of P450s is investigated using human hepatocytes in the drug development process, there are some disadvantages, such as the decline of the enzyme activity during culture. In the present study, we examined the in vivo induction potency in chimeric mice with humanized liver, which was recently established in Japan to clarify whether this chimeric mouse model would be more suitable for human induction studies. Rifampicin and 3-methylcholanthrene (3-MC) were used in vivo as typical P450 inducers in the chimeric mice. The expression levels of human CYP3A4 mRNA and CYP3A4 protein and dexamethasone 6-hydroxylase activity, specific for human CYP3A4, were increased 8- to 22-, 3- to 10-, and 5- to 12-fold, respectively, by treatment with rifampicin. In addition, the expression levels of human CYP1A2 mRNA and CYP1A2 protein were also increased 2- to 9- and 5-fold, respectively, by treatment with 3-MC. Although other human P450s are expressed in the chimeric mice, there were few effects by the treatment of rifampicin and 3-MC on the mRNA, protein, and enzyme activity of those P450s. It was demonstrated that human P450s expressed in the chimeric mice with humanized liver were induced by rifampicin and 3-MC. This chimeric mouse model may be a useful animal model to estimate and predict the in vivo induction of P450s in humans.