Induction of CYP3A1 by dexamethasone and pregnenolone-16alpha-carbonitrile in pregnant rat and fetal livers and placenta

Exp Toxicol Pathol. 2003 Mar;54(4):273-9. doi: 10.1078/0940-2993-00263.

Abstract

Cytochrome P450 (CYP) 3A1 was detected in the cytoplasm of giant cells in the trophoblastic region of rat placenta through pregnancy (Ejiri et al. 2001). In the present study, changes in the expression of CYP3A1 protein as well as in the histology of pregnant rat and fetal livers and placenta after treatment with dexamethasone (DEX) or pregnenolone-16alpha-carbonitrile (PCN), well-known CYP3A1 inducers, at 16 day of gestation (DG) (DEX1 and PCN1 groups: 100 mg/kg) or from 13 to 16 DG (DEX4 group: 25 mg/kg/day; PCN4 group: 50 mg/kg/day). All animals were killed at 17 DG, and Western blot and immunohistochemical analyses on CYP3A1 expression and histological examination were done. Western blot analysis revealed that PCN induced CYP3A1 more clearly than DEX and that the induction was most prominent in the fetal liver and lowest in the placenta. Except for the placenta, changes in the immunohistochemical stainability for CYP3A1 almost corresponded to those in the expression of CYP3A1 by Western blot analysis. In addition, swelling and and/or vacuolization of hepatocytes were generally observed in the mother and fetal livers showing increased expression of CYP3A1. These results suggest that DEX and PCN might pass through the placenta with no prominent induction of CYP3A1 at the placenta and be distributed to the fetal liver rapidly, resulting in high induction of CYP3A1 in the fetal liver.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / biosynthesis*
  • Blotting, Western
  • Cytochrome P-450 CYP3A
  • Dexamethasone / pharmacology*
  • Enzyme Activators / pharmacology*
  • Enzyme Induction / drug effects*
  • Female
  • Fetus / drug effects
  • Fetus / enzymology
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Immunohistochemistry
  • Liver / drug effects
  • Liver / embryology
  • Liver / enzymology
  • Placenta / cytology
  • Placenta / drug effects
  • Placenta / enzymology
  • Pregnancy
  • Pregnancy, Animal / drug effects*
  • Pregnenolone Carbonitrile / pharmacology*
  • Rats
  • Rats, Inbred F344

Substances

  • Enzyme Activators
  • Pregnenolone Carbonitrile
  • Dexamethasone
  • Aryl Hydrocarbon Hydroxylases
  • Cyp3a23-3a1 protein, rat
  • Cytochrome P-450 CYP3A