Expression and induction of CYP3As in human fetal hepatocytes.
CYP3A4 and CYP3A7 mRNA expression levels were markedly up-regulated by dexamethasone (DEX), but not by rifampicin (RIF). CYP3A5 mRNA level was not increased significantly by DEX, RIF, or phenobarbital. Testosterone 6beta-hydroxylase activity was induced to about 2-fold of control by DEX. However, concomitant treatment with RIF did not alter DEX-mediated induction of CYP3A mRNA expression and testosterone 6beta-hydroxylase activity. DEX-mediated induction of CYP3A mRNA was suppressed in a dose-dependent manner by RU486, a glucocorticoid receptor (GR) antagonist. At 5microM RU486, DEX-mediated induction of CYP3A4, CYP3A5, and CYP3A7 mRNA expression was inhibited almost completely. These results suggest that, in human fetal hepatocytes, PXR is not involved in DEX-mediated induction of CYP3A4 and CYP3A7, and that the induction is mediated directly by GR.
Matsunaga
Tamihide
T
Division of Pharmacy, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto 390-8621, Japan. t-matsu@hsp.md.shinshu-u.ac.jp
Maruyama
Masataka
M
Harada
Eri
E
Katsuyama
Yoshihiko
Y
Sugihara
Nobuhiro
N
Ise
Hirohiko
H
Negishi
Naoki
N
Ikeda
Uichi
U
Ohmori
Shigeru
S
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D007313:Insecta / Q000166:cytology; D008861:Microsomes / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D012293:Rifampin / Q000494:pharmacology; D014212:Tretinoin / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D014212:Tretinoin; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D012293:Rifampin; D010634:Phenobarbital