Development of mice exhibiting hepatic microsomal activity of human CYP3A4 comparable to that in human liver microsomes by intravenous administration of an adenovirus vector expressing human CYP3A4.
Cytochrome P450 3A4 (CYP3A4) plays a crucial role in the pharmacokinetic and safety profiles of drugs. However, it is difficult to properly predict the pharmacokinetics and hepatotoxicity of drugs in humans using data from experimental animals, because the catalytic activities of CYP3A4 and other drug-metabolizing enzymes differ between human and animal organs. In order to easily generate an animal model for proper evaluation of human CYP3A4-mediated drug metabolism, we developed a human CYP3A4-expressing adenovirus (Ad) vector based on our novel Ad vector exhibiting significantly lower hepatotoxicity (Ad-E4-122aT-hCYP3A4). Intravenous administration of Ad-E4-122aT-hCYP3A4 at a dose of 2 × 10(11) virus particles/mouse produced a mouse exhibiting human CYP3A4 activity at a level similar to that in the human liver, as shown in the dexamethasone metabolic experiment using liver microsomes. The area under the curve (AUC) of 6βOHD was 2.7-fold higher in the Ad-E4-122aT-hCYP3A4-administered mice, compared with the mice receiving a control Ad vector. This Ad vector-expressing human CYP3A4 would thus be a powerful tool for evaluating human CYP3A4-mediated drug metabolism in the livers of experimental animals.
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University.
Shuichi
S
Kuno
Fuminori
F
Sakurai
Kahori
K
Shimizu
Naoya
N
Matsumura
Soonih
S
Kim
Hitoshi
H
Watanabe
Katsuhisa
K
Tashiro
Masashi
M
Tachibana
Tsuyoshi
T
Yokoi
Hiroyuki
H
Mizuguchi
D000260:Adenoviruses, Human / Q000235:genetics*; D061605:Administration, Intravenous; D000818:Animals; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism*; D003907:Dexamethasone / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics*; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D023421:Models, Animal
D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human