Induction of cytochrome P450 isozymes by phenobarbital in pregnant rat and fetal livers and placenta.
Cytochrome P450 (CYP) isozymes are important in metabolizing xenobiotics. They are found in extrahepatic tissues such as placenta as well as liver. Previously, we reported that CYP3A1 was detected in the cytoplasm of giant cells in the trophoblastic region of placenta of rats through pregnancy. In this study, we examined the changes in the expression of CYP proteins in the pregnant rat and fetal livers and placenta after treatment with phenobarbital (PB), one of the antiepileptic drugs which is well known to induce several phase I and phase II drug metabolizing enzymes in the liver. Namely, F344 pregnant rats were treated with PB (80 mg/kg, i.p.) from 13 days of gestation (DG) to 16 DG. All animals were sacrificed on 17 DG, and Western blot analysis and immunohistochemical staining on nine CYP proteins (CYP1A1, CYP2B1, CYP2C6, CYP2C12, CYP2D1, CYP2D4, CYP2E1, CYP3A1, and CYP4A1) and histological examination were done in the dam's liver, placenta, and the fetal liver. Western blot analysis revealed that CYP3A1 protein was significantly induced, CYP2B1 protein was detected, and CYP2D1 protein was significantly decreased in the dam's liver after PB-treatment. In placenta, only CYP3A1 was detected with no difference between control and PB-treated animals. The results of immunohistochemical staining corresponded closely to those of Western blot analysis in the dam's liver and placenta. In the fetal liver, CYP3A1 and CYP2C6 proteins were significantly induced after the PB-treatment, but their immunostainability was not prominent. The present results are considered useful as a basis for further investigation of drug metabolism in pregnant animals.
Ejiri
Noriko
N
Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Katayama
Kei-ichi
K
Doi
Kunio
K
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005333:Fetus; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology*; D010920:Placenta / Q000187:drug effects* / Q000201:enzymology; D011247:Pregnancy; D051381:Rats
D000927:Anticonvulsants; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital