PMID- 12813002
OWN - NLM
STAT- MEDLINE
DCOM- 20040324
LR  - 20240413
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 139
IP  - 4
DP  - 2003 Jun
TI  - Upregulation of cytochromes P450 2B in rat liver by orphenadrine.
PG  - 787-96
AB  - 1 The alkylamine drug orphenadrine (ORPH) is an inducer and inhibitor of the 
      microsomal cytochrome P450 (CYP) system in mammals. This study evaluated the 
      selectivity of CYP induction by ORPH in rat liver. 2 Immunoblot analysis 
      indicated that ORPH was a selective inducer of the phenobarbitone (PB)-inducible 
      CYP2B in rat liver. CYP2B protein was increased to approximately 14-fold of 
      levels in untreated rat liver. By comparison PB increased CYP2B expression 
      40-fold. Corresponding increases in the activity of CYP2B-dependent 
      androstenedione 16beta-hydroxylation were measured in microsomes from ORPH and 
      PB-induced rats. 3 Northern analysis indicated that CYP2B1/2 mRNA was increased 
      in ORPH-induced rat liver. Consistent with this finding, ORPH was found to 
      activate a PB-responsive enhancer module in constitutive androstane receptor 
      (CAR)-transfected Hep G2 cells. 4 Other alkylamines like troleandomycin impair 
      CYP turnover. We tested whether ORPH induction of CYP2B may include a 
      post-translational component. In PB-pretreated animals ORPH administration 
      delayed the loss of CYP2B after PB withdrawal, but no evidence for altered 
      turnover was found. 5 These studies establish ORPH as a selective inducer of 
      CYP2B in rat liver. Induction appears to be mediated pretranslationally by CAR 
      activation of CYP2B gene transcription. Post-translational stabilisation by an 
      ORPH metabolite does not elicit induction. Induction of CYP2B may influence 
      pharmacokinetic interactions involving ORPH.
FAU - Murray, Michael
AU  - Murray M
AD  - Department of Physiology and Pharmacology, School of Medical Sciences, University 
      of New South Wales, Sydney, NSW 2052, Australia. M.Murray@unsw.edu.au
FAU - Fiala-Beer, Eva
AU  - Fiala-Beer E
FAU - Sutton, Dylan
AU  - Sutton D
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Cytochrome P-450 Enzyme Inhibitors)
RN  - 6051-87-2 (beta-Naphthoflavone)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - AL805O9OG9 (Orphenadrine)
RN  - YOW8V9698H (Dimethyl Sulfoxide)
RN  - YQE403BP4D (Phenobarbital)
SB  - IM
MH  - Animals
MH  - Cytochrome P-450 Enzyme Inhibitors
MH  - Cytochrome P-450 Enzyme System/*drug effects/*genetics
MH  - Dexamethasone/administration & dosage/pharmacokinetics
MH  - Dimethyl Sulfoxide/administration & dosage/pharmacokinetics
MH  - Enzyme Induction/drug effects
MH  - Gene Expression Regulation/drug effects/physiology
MH  - Injections, Intraperitoneal
MH  - Male
MH  - Microsomes, Liver/*enzymology
MH  - Orphenadrine/administration & dosage/metabolism/*pharmacokinetics
MH  - Phenobarbital/administration & dosage/metabolism/pharmacokinetics
MH  - Protein Biosynthesis/drug effects/physiology
MH  - Rats
MH  - Rats, Wistar
MH  - Up-Regulation/*drug effects/physiology
MH  - beta-Naphthoflavone/administration & dosage/metabolism/pharmacokinetics
PMC - PMC1573901
EDAT- 2003/06/19 05:00
MHDA- 2004/03/25 05:00
PMCR- 2004/06/01
CRDT- 2003/06/19 05:00
PHST- 2003/06/19 05:00 [pubmed]
PHST- 2004/03/25 05:00 [medline]
PHST- 2003/06/19 05:00 [entrez]
PHST- 2004/06/01 00:00 [pmc-release]
AID - 0705305 [pii]
AID - 10.1038/sj.bjp.0705305 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2003 Jun;139(4):787-96. doi: 10.1038/sj.bjp.0705305.