Document Detail


Suppression of hepatic CYP3A1/2 and CYP2C11 by cyclosporine is not mediated by altering growth hormone levels.
MedLine Citation:
PMID:  12649386     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cyclosporine (CsA) suppresses drug metabolism by decreasing cytochrome P450 (P450) enzyme levels in rat liver. Growth hormone (GH) is known to pretranslationally regulate P450 expression. Thus, the suppression of P450 by CsA may involve GH as an intermediate. To address this question, we examined the effects of administering exogenous GH via twice daily subcutaneous injections and in conjunction with chronic subcutaneous CsA administration for 14 days on hepatic P450 expression. CsA alone decreased CYP3A1/2 and CYP2C11 significantly, in a manner similar to that previously found. When administered in the absence of CsA, GH also suppressed CYP3A1/2 and CYP2C11 protein levels as compared with GH vehicle. In the presence of CsA, GH did not cause further suppression of either CYP3A1/2 or CYP2C11 expression when compared with CsA treatment with GH vehicle. Testosterone in vitro catalytic assays confirmed that CsA and GH separately cause significant decreases in activity levels. Also, the concomitant administration of GH and CsA caused lowered production of 16alpha-, 2alpha-, 6beta-, and 2beta-hydroxytestosterone as compared with the administration of GH with CsA vehicle and as compared with the administration of GH vehicle with CsA. This study shows that GH is a dominating factor over CsA in determining hepatic P450 expression and activity. In addition, CsA does not seem to alter GH levels as a mediating event in suppressing P450 expression and activity. Since CsA given in combination with GH further suppressed P450 activity as compared with CsA given in combination with vehicle, this suggests that changes in hormonal status are likely to be one of the many factors that is responsible for the lack of a clear association between cyclosporine dosing and markers of toxicity.
Authors:
Shirley K Lu; Shellie M Callahan; Lane J Brunner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  305     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2003 Apr 
Date Detail:
Created Date:  2003-03-21     Completed Date:  2003-04-22     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  331-7     Citation Subset:  IM    
Affiliation:
Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712-1074, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors,  metabolism
Cyclosporine / blood,  pharmacology*
Cytochrome P-450 Enzyme System / antagonists & inhibitors*,  metabolism
Drug Combinations
Growth Hormone / blood,  pharmacology*
Hydroxylation
Kidney Function Tests
Liver / drug effects*,  enzymology
Male
Membrane Proteins*
Rats
Rats, Sprague-Dawley
Steroid 16-alpha-Hydroxylase / antagonists & inhibitors,  metabolism
Testosterone / metabolism
Grant Support
ID/Acronym/Agency:
GM 60910/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Drug Combinations; 0/Membrane Proteins; 58-22-0/Testosterone; 59865-13-3/Cyclosporine; 9002-72-6/Growth Hormone; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C11 protein, rat; EC 1.14.14.1/Cyp3a1 protein, rat; EC 1.14.14.1/Cyp3a2 protein, rat; EC 1.14.14.1/Steroid 16-alpha-Hydroxylase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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