Different diets cause alterations in the enteric environment and trigger changes in the expression of hepatic cytochrome P450 3A, a drug-metabolizing enzyme.
Changes in the expression level and activity of cytochrome P450 (CYP) in the liver are caused by various factors and affect the pharmacokinetics of drugs. The purpose of this study was to determine whether the expression of CYP3A is affected by a high-fat diet. In addition, we examined whether the type of diet given to mice could produce changes in the expression level and activity of CYP3A. Mice were fed a purified diet containing 10 kcal% lard (control group) or 60 kcal% lard (HF group) or regular mouse chow containing 13 kcal% of fat (MF group) for 4 weeks. No significant differences were observed in the hepatic CYP3A protein expression level between the HF group and the control group. The CYP3A protein expression in the MF group was significantly higher than that observed in the control group. In the MF group, the area under the curve (AUC) of intraperitoneally administered triazolam was lower. Because lithocholic acid (LCA) is known to increase hepatic CYP3A expression, the levels of Clostridium sordellii and LCA in the feces were measured. In the MF group, the levels of Clostridium sordellii and LCA were higher. It has been demonstrated that a high-fat diet does not cause any changes in hepatic CYP3A expression. In addition, the different diets caused alterations in the enteric environment, which triggered changes in CYP3A expression. Therefore, it is necessary to carefully consider the type of feed while performing animal experiments to evaluate the pharmacokinetics of drugs.
Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Tokyo 142-8501, Japan.
Masataka
M
Tajima
Nobutomo
N
Ikarashi
Shintaro
S
Igeta
Takahiro
T
Toda
Makoto
M
Ishii
Yoshikazu
Y
Tanaka
Yoshiaki
Y
Machida
Wataru
W
Ochiai
Harumi
H
Yamada
Kiyoshi
K
Sugiyama
D052436:Adipose Tissue, White / Q000254:growth & development; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D059305:Diet, High-Fat; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005243:Feces / Q000737:chemistry; D008095:Lithocholic Acid / Q000378:metabolism; D008099:Liver / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D008861:Microsomes / Q000378:metabolism; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism; D014229:Triazolam / Q000493:pharmacokinetics; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D002784:Cholesterol; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D005230:Fatty Acids, Nonesterified; D008095:Lithocholic Acid; D008565:Membrane Proteins; D012333:RNA, Messenger; D014229:Triazolam; D014280:Triglycerides; C496508:Cyp3a11 protein, mouse