Placental transfer of the hypolipidemic drug, clofibrate, induces CYP4A expression in 18.5-day fetal rats.
Rats at day 15.5 of gestation were dosed intraperitoneally with 300 mg.kg-1 of clofibrate for three consecutive days at 24-hr intervals and were culled 24 hr after the final injection. This regime produced maximal induction of the cytochrome P4504A (CYP4A) mRNAs in the maternal liver and kidney and in 18.5-day fetal tissues. The maternal hepatic and renal CYP4A mRNA levels had risen 12- and 2-fold, respectively, above the constitutive levels seen in untreated pregnant rats at an equivalent stage of gestation. Clofibrate was capable of traversing the placenta and modulating the fetal CYP4A mRNA expression as demonstrated by a 3-fold elevation in the mRNA levels in those fetuses explanted from drug-induced mothers, compared with those fetuses removed from untreated mothers. The CYP4A mRNAs were demonstrated in the fetal liver via dot-blot and Northern blot analyses. In addition, low levels of CYP4A mRNA expression were detected in the induced placenta via Northern blot analysis. Western blot analysis revealed that the CYP4A protein levels increased in the maternal liver and in the kidney and fetal livers after exposure to clofibrate. Peroxisome proliferation, a phenomenon associated with induction of CYP4A1 expression in rodents, was demonstrated in both maternal and fetal livers, with the use of light and electron microscopy.
Simpson
A E
AE
Knoll Pharmaceuticals, Nottingham, UK.
Brammar
W J
WJ
Pratten
M K
MK
Cockcroft
N
N
Elcombe
C R
CR
D000818:Animals; D001483:Base Sequence; D002994:Clofibrate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D015342:DNA Probes; D004790:Enzyme Induction; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000201:enzymology; D005865:Gestational Age; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000196:embryology / Q000201:enzymology; D008431:Maternal-Fetal Exchange; D008830:Microbodies / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics*; D008969:Molecular Sequence Data; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D015342:DNA Probes; D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D002994:Clofibrate