Consumption of a high-fat diet during pregnancy decreases the activity of cytochrome P450 3a in the livers of offspring.
Recent studies have reported that a high-fat diet during pregnancy exerts various effects on the foetus and newborn. The purpose of this study was to clarify the effects of a high-fat diet during pregnancy on the activity of hepatic cytochrome P450 (Cyp) 3a in offspring in mice. The protein expression level and activity of Cyp3a in the livers of 6-week-old mice born to mothers that were given a high-fat diet during pregnancy (HF group) decreased significantly compared with the Control group. Triazolam, which is a substrate of Cyp3a, was intraperitoneally administered to the mice in the HF group. Compared with the Control group, an increase in the area under the plasma concentration-time curve and a decrease in total clearance were observed in the HF group. The hepatic constitutive androstane receptor (CAR) mRNA expression level in the HF group was significantly lower than that in the Control group. An increase in phosphorylation of extracellular signal-regulated kinase (ERK) was also observed in the HF group. The results of this study revealed that a high-fat diet during pregnancy causes an increase in ERK phosphorylation and a decrease in the expression level of CAR in the livers of offspring, which leads to decreased Cyp3a expression and activity. The results suggest that individual differences in pharmacokinetics may not only be expressed by genetic predisposition but also by a mother's living environment during pregnancy.
Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Masataka
M
Tajima
Nobutomo
N
Ikarashi
Yukari
Y
Imahori
Takehiro
T
Okaniwa
Kanako
K
Saruta
Makoto
M
Ishii
Yoshiki
Y
Kusunoki
Risako
R
Kon
Takahiro
T
Toda
Wataru
W
Ochiai
Harumi
H
Yamada
Kiyoshi
K
Sugiyama
D000818:Animals; D000831:Animals, Newborn; D019540:Area Under Curve; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism; D001835:Body Weight / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects* / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000201:enzymology / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D014229:Triazolam / Q000493:pharmacokinetics
D001786:Blood Glucose; D004041:Dietary Fats; D012333:RNA, Messenger; D014229:Triazolam; D051544:Cytochrome P-450 CYP3A; D048049:Extracellular Signal-Regulated MAP Kinases