Mechanisms of CYP3A induction by glucocorticoids in human fetal liver cells.
Human fetal liver (HFL) cells express major drug metabolic enzymes CYP3A4, CYP3A5 and CYP3A7. In the fetal hepatocytes, betamethasone and dexamethasone (DEX) markedly enhanced the expression levels of CYP3A4 and CYP3A7 mRNAs and slightly increased the expression level of CYP3A5 mRNA. Interestingly, a high correlation between the CYP3A induction ability and the intensity of anti-inflammatory effect was observed. Human glucocorticoid receptor (GR)-small interfering RNA clearly attenuated the expression level of GR mRNA, and diminished the DEX-stimulated CYP3A4, CYP3A5 and CYP3A7 expression in HFL cells. These findings indicate that GR mediates the induction of CYP3A4 and CYP3A7 expression in human fetal hepatocytes as well as the CYP3A5.
Department of Pharmacy, Shinshu University Hospital, Matsumoto, Japan.
Tamihide
T
Matsunaga
Masataka
M
Maruyama
Tsutomu
T
Matsubara
Kiyoshi
K
Nagata
Yasushi
Y
Yamazoe
Shigeru
S
Ohmori
D001623:Betamethasone / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005333:Fetus; D005938:Glucocorticoids / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000378:metabolism
D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D001623:Betamethasone; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A