Document Detail

Induction of rabbit lung CYP4A4 prostaglandin omega-hydroxylase by various steroid hormones.
MedLine Citation:
PMID:  11516164     Owner:  NLM     Status:  MEDLINE    
Cytochrome P4504A4 (CYP4A4) is expressed at low basal levels in adult rabbit lungs, but is significantly induced during pregnancy by an unknown mechanism. As the gradual rise in CYP4A4 levels appears to coincide with the progressive increase in several steroid hormones throughout pregnancy, we examined the induction of CYP4A4 after treatment with various steroid hormones by monitoring both the CYP4A4 mRNA level and the CYP4A4-specific prostaglandin E(1) (PGE(1)) omega-hydroxylation reaction in rabbit lung microsomes. Treatment with progesterone and/or a synthetic glucocorticoid (dexamethasone) resulted in a significant increase in PGE(1) omega-hydroxylase activity, whereas estradiol, aldosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate did not. These studies indicated that dexamethasone was a more potent inducer of CYP4A4 than progesterone. Simultaneous injection of dexamethasone and glucocorticoid/progesterone antagonists (RU38486, RU40555, or RU43044) inhibited the increase in PGE(1) omega-hydroxylase activity as well as mRNA levels by approximately 50%. In addition, simultaneous treatment with both dexamethasone and progesterone did not result in an additive or synergistic effect on PGE(1) omega-hydroxylase activity. These data indicate that, while distinctive receptors for glucocorticoid and/or progesterone are involved, induction may also require common or interacting regulatory elements (yet to be determined) in the CYP4A4 gene. These findings implicate both of these steroid receptors (PR/GR) in the induction of CYP4A4 in rabbit lung.
T J McCabe; L J Roman; B S Masters
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Archives of biochemistry and biophysics     Volume:  393     ISSN:  0003-9861     ISO Abbreviation:  Arch. Biochem. Biophys.     Publication Date:  2001 Sep 
Date Detail:
Created Date:  2001-08-22     Completed Date:  2001-10-11     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0372430     Medline TA:  Arch Biochem Biophys     Country:  United States    
Other Details:
Languages:  eng     Pagination:  78-86     Citation Subset:  IM    
Department of Pharmacology, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06536, USA.
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MeSH Terms
Alprostadil / metabolism
Cytochrome P-450 Enzyme System / biosynthesis*,  genetics
Dexamethasone / pharmacology
Enzyme Induction / drug effects
Hormone Antagonists / pharmacology
Lung / drug effects*,  enzymology*
Microsomes / drug effects,  enzymology
Mixed Function Oxygenases / biosynthesis*,  genetics
Progesterone / pharmacology
RNA, Messenger / genetics,  metabolism
Receptors, Glucocorticoid / antagonists & inhibitors
Receptors, Progesterone / antagonists & inhibitors
Steroids / pharmacology*
Grant Support
Reg. No./Substance:
0/Hormone Antagonists; 0/RNA, Messenger; 0/Receptors, Glucocorticoid; 0/Receptors, Progesterone; 0/Steroids; 50-02-2/Dexamethasone; 57-83-0/Progesterone; 745-65-3/Alprostadil; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC omega hydroxylases

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