PMID- 17344340
OWN - NLM
STAT- MEDLINE
DCOM- 20070905
LR  - 20181211
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 35
IP  - 6
DP  - 2007 Jun
TI  - Molecular mechanism of basal CYP3A4 regulation by hepatocyte nuclear factor 
      4alpha: evidence for direct regulation in the intestine.
PG  - 946-54
AB  - Cytochrome P450 3A4 plays an outstanding role in the metabolism of clinically 
      used drugs and shows a marked interindividual variability in expression even in 
      the absence of inducing agents. Thus, regulation of basal expression contributes 
      considerably to variability. The nuclear receptor hepatocyte nuclear factor 
      4alpha (HNF4alpha) was previously shown to be associated with basal hepatic 
      CYP3A4 expression. As how HNF4alpha regulates basal expression of CYP3A4 still 
      remains elusive, we systematically screened 12.5 kilobase pairs (kb) of the 
      CYP3A4 5' upstream region for activation by the receptor in the human intestinal 
      cell line LS174T. In this study, we newly identified two widely separated regions 
      mediating the activation by HNF4alpha: a far distal region at -9.0 kb and the 
      proximal promoter region at approximately -0.2 kb. By gel shift experiments and 
      transient transfections, we characterized direct repeat (DR) 1-type motifs in 
      both regions as functional HNF4alpha response elements. Cooperation of the two 
      regions was shown to be required for maximal activation by HNF4alpha. The effect 
      of HNF4alpha was antagonized by chicken ovalbumin upstream promoter transcription 
      factor II, which was shown to bind to one of the DR1 motifs. Furthermore, 
      activation of CYP3A4 via the DR1 element in the proximal promoter depends on an 
      additional, yet unknown, factor, which is binding at approximately -189 base 
      pairs. Physiological relevance of this position for activation by HNF4alpha in 
      vivo is suggested by the presence of a binding activity in small intestine 
      similar to that in LS174T cells. In summary, we here have elucidated a molecular 
      mechanism of direct regulation of CYP3A4 by HNF4alpha, which is probably specific 
      for the intestine.
FAU - Tegude, Heike
AU  - Tegude H
AD  - Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 
      112, D-70376 Stuttgart, Germany.
FAU - Schnabel, Anke
AU  - Schnabel A
FAU - Zanger, Ulrich M
AU  - Zanger UM
FAU - Klein, Kathrin
AU  - Klein K
FAU - Eichelbaum, Michel
AU  - Eichelbaum M
FAU - Burk, Oliver
AU  - Burk O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070307
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (HNF4A protein, human)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (RNA, Messenger)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.14.14.55 (CYP3A4 protein, human)
SB  - IM
MH  - Binding Sites
MH  - Cell Line, Tumor
MH  - Cytochrome P-450 CYP3A
MH  - Cytochrome P-450 Enzyme System/genetics/*metabolism
MH  - Hepatocyte Nuclear Factor 4/genetics/*metabolism
MH  - Humans
MH  - Intestinal Mucosa/*metabolism
MH  - Liver/metabolism
MH  - Promoter Regions, Genetic
MH  - RNA, Messenger/metabolism
MH  - Response Elements
EDAT- 2007/03/09 09:00
MHDA- 2007/09/06 09:00
CRDT- 2007/03/09 09:00
PHST- 2007/03/09 09:00 [pubmed]
PHST- 2007/09/06 09:00 [medline]
PHST- 2007/03/09 09:00 [entrez]
AID - dmd.106.013565 [pii]
AID - 10.1124/dmd.106.013565 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2007 Jun;35(6):946-54. doi: 10.1124/dmd.106.013565. Epub 2007 
      Mar 7.