PMID- 11950789
OWN - NLM
STAT- MEDLINE
DCOM- 20020912
LR  - 20190607
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 30
IP  - 5
DP  - 2002 May
TI  - Induction of CYP3A expression by dehydroepiandrosterone: involvement of the 
      pregnane X receptor.
PG  - 570-5
AB  - Dehydroepiandrosterone (DHEA) is a steroid produced by the human adrenal gland. 
      Administration of pharmacological doses of DHEA to rats changes expression of 
      many genes, including the cytochrome P450 family members CYP4A1 and CYP3A23. It 
      is known that induction of CYP4A expression by DHEA requires the peroxisome 
      proliferator-activated receptor alpha (PPAR(alpha)). In the current study, 
      PPAR(alpha)-null mice were used to examine the role of PPAR(alpha) in expression 
      of CYP3A. In wild-type mice, 150 mg/kg DHEA-sulfate induced Cyp4a and Cyp3a11 
      mRNAs by 5- and 2-fold, respectively. Induction of Cyp4a expression by 
      DHEA-sulfate was not observed in PPAR(alpha)-null mice, whereas induction of 
      Cyp3a11 expression by DHEA-sulfate was similar between genotypes. This suggests 
      that PPAR(alpha) is not involved in induction of Cyp3a11 expression by DHEA. 
      Because expression of CYP3A family members can be induced by activation of 
      another member of the nuclear receptor superfamily, the pregnane X receptor 
      (PXR), we examined the ability of DHEA to activate PXR. In transient transfection 
      assays, DHEA and its metabolites androst-5-ene-3beta,17beta-diol (ADIOL), 
      androst-5-ene-3,17-dione, and androst-4-ene-3,17-dione were activators of PXR. 
      Maximal induction of a PXR-responsive reporter gene of approximately 3-fold was 
      observed at concentrations of 50 to 100 microM, indicating that these steroids 
      are relatively weak activators of PXR. Human and murine PXR exhibited different 
      specificities for DHEA and its metabolites. ADIOL activated reporter gene 
      expression in the presence of murine but not human PXR. Results of these studies 
      suggest that the induction of rodent CYP3A expression upon treatment with high 
      doses of DHEA occurs through activation of PXR.
FAU - Ripp, Sharon L
AU  - Ripp SL
AD  - Department of Biochemistry and Molecular Biology, University of Louisville School 
      of Medicine, Louisville, Kentucky 40292, USA.
FAU - Fitzpatrick, Jennifer L
AU  - Fitzpatrick JL
FAU - Peters, Jeffrey M
AU  - Peters JM
FAU - Prough, Russell A
AU  - Prough RA
LA  - eng
GR  - CA 89607/CA/NCI NIH HHS/United States
GR  - DK54774/DK/NIDDK NIH HHS/United States
GR  - F32 ES05927/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Membrane Proteins)
RN  - 0 (Pregnane X Receptor)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Receptors, Steroid)
RN  - 0 (Transcription Factors)
RN  - 409J2J96VR (Androstenedione)
RN  - 459AG36T1B (Dehydroepiandrosterone)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - 95PS51EMXY (Androstenediol)
RN  - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
RN  - EC 1.14.14.1 (Cyp3a11 protein, mouse)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.5.- (Oxidoreductases, N-Demethylating)
SB  - IM
MH  - Androstenediol/pharmacology
MH  - Androstenedione/pharmacology
MH  - Animals
MH  - *Aryl Hydrocarbon Hydroxylases
MH  - Cell Line
MH  - Cytochrome P-450 CYP3A
MH  - Cytochrome P-450 Enzyme System/*biosynthesis
MH  - Dehydroepiandrosterone/*pharmacology
MH  - Enzyme Induction
MH  - Humans
MH  - Membrane Proteins
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Oxidoreductases, N-Demethylating/*biosynthesis
MH  - Pregnane X Receptor
MH  - Receptors, Cytoplasmic and Nuclear/agonists/genetics/*physiology
MH  - Receptors, Steroid/agonists/*physiology
MH  - Transcription Factors/genetics/physiology
EDAT- 2002/04/16 10:00
MHDA- 2002/09/13 10:01
CRDT- 2002/04/16 10:00
PHST- 2002/04/16 10:00 [pubmed]
PHST- 2002/09/13 10:01 [medline]
PHST- 2002/04/16 10:00 [entrez]
AID - 10.1124/dmd.30.5.570 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2002 May;30(5):570-5. doi: 10.1124/dmd.30.5.570.