Effect of pregnancy on cytochrome P450 3a and P-glycoprotein expression and activity in the mouse: mechanisms, tissue specificity, and time course.
The plasma concentrations of orally administered anti-human immunodeficiency virus protease inhibitors are significantly reduced during human and mouse pregnancy. We have shown that in the mouse, at gestational day 19, this reduction is due to increased hepatic cytochrome P450 3a (Cyp3a) protein expression and activity. In the current study, we investigated the mechanisms by which Cyp3a activity is increased by pregnancy and the time course of change in expression of Cyp3a and P-glycoprotein (P-gp) in various tissues. We found that hepatic transcripts of Cyp3a16, Cyp3a41, and Cyp3a44 were significantly increased during pregnancy, whereas those of Cyp3a11 and Cyp3a25 were significantly decreased. This resulted in a net increase in Cyp3a protein expression and activity in the liver during pregnancy. The increase in Cyp3a41 and Cyp3a44 transcripts was positively correlated (p < 0.05) with hepatocyte nuclear factor 6 and estrogen receptor-alpha transcripts. The pregnancy-related factors that transcriptionally activated mouse Cyp3a isoforms also activated the human CYP3A4 promoter in pregnant CYP3A4-promoter-luciferase transgenic (CYP3A4-tg) mice. In contrast, intestinal Cyp3a protein expression was not significantly affected by pregnancy. No change in P-gp protein expression was observed in the liver or kidney during pregnancy, although a significant decrease was observed in the placenta. Because hepatic CYP3A activity also seems to be induced during human pregnancy, the mouse (including CYP3A4-tg mouse) seems to be an excellent animal model to determine the molecular mechanisms for such an induction.
Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
Huixia
H
Zhang
Xiaohui
X
Wu
Honggang
H
Wang
Andrei M
AM
Mikheev
Qingcheng
Q
Mao
Jashvant D
JD
Unadkat
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D006801:Humans; D007422:Intestines / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D014157:Transcription Factors; D051544:Cytochrome P-450 CYP3A