Document Detail


Cytochrome-P-450-dependent metabolism of retinoic acid in rat skin microsomes: inhibition by ketoconazole.
MedLine Citation:
PMID:  2856164     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Epidermal microsomes, prepared from neonatal Wistar or Sprague-Dawley rats, show low levels of retinoic acid (RA) metabolism. The specific activities (as fmol/min/mg protein) of epidermal microsomes, using [15-14C]-RA as substrate, are 232 (Wistar rats) and 222 (Sprague-Dawley rats). Topical application of RA (1 mg) on 4-day-old rats induces a 3.3- and 3.9-fold increase in epidermis microsomal RA metabolism. A 4.6- to 8.1-fold increase is observed 24 h after topical application of 3-methylcholanthrene (0.5 mg). By contrast, phenobarbital (1 mg topically) has a much smaller inducing effect. So far the chemical structure of the metabolites has not been identified. The Rf values of two major compounds correspond with those of 4-hydroxy- and 4-ketoretinoic acid, formed after incubation of hamster liver microsomes in the presence of [15-14C]-RA. The RA metabolism in rat epidermal microsomes shows the typical characteristics of a cytochrome-P-450 (P450)-dependent enzyme system, i.e. a requirement for NADPH and oxygen and inhibition by CO and SKF-525A. Ketoconazole and miconazole, imidazole antifungal agents and inhibitors of some fungal and mammalian P450-dependent enzymes, inhibit in vitro RA metabolism by rat epidermal microsomes. 50% inhibition is achieved at 6.5 X 10(-7) and greater than or equal to 10(-5) mol/l, respectively. The triazole antifungal agent, itraconazole, has no effect at concentrations up to 10(-5) mol/l. Topical treatment of 4-day-old Wistar rats with ketoconazole, at doses of 1,5 and 10 mg/kg, 1 h before the application of RA (1 mg/rat) results in a dose-dependent inhibition of RA metabolism by epidermal microsomes, prepared 24 h later. Our data show a P450-dependent RA metabolism in rat epidermal microsomes and suggest that ketoconazole may prove to be effective in maintaining biologically active levels of RA in epidermal cells.
Authors:
H Vanden Bossche; G Willemsens; P A Janssen
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Skin pharmacology : the official journal of the Skin Pharmacology Society     Volume:  1     ISSN:  1011-0283     ISO Abbreviation:  Skin Pharmacol.     Publication Date:  1988  
Date Detail:
Created Date:  1990-04-13     Completed Date:  1990-04-13     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8810069     Medline TA:  Skin Pharmacol     Country:  SWITZERLAND    
Other Details:
Languages:  eng     Pagination:  176-85     Citation Subset:  IM    
Affiliation:
Janssen Research Foundation, Beerse, Belgium.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn
Antimetabolites / pharmacology
Biotransformation
Carbon Monoxide / pharmacology
Cricetinae
Cytochrome P-450 Enzyme System / metabolism*
Itraconazole
Ketoconazole / analogs & derivatives,  pharmacology*
Mesocricetus
Miconazole / pharmacology
Microsomes / drug effects,  enzymology,  metabolism*
Microsomes, Liver / metabolism
Oxygen / pharmacology
Rats
Rats, Inbred Strains
Skin / drug effects,  enzymology,  metabolism*
Tretinoin / metabolism*
Chemical
Reg. No./Substance:
0/Antimetabolites; 22916-47-8/Miconazole; 302-79-4/Tretinoin; 630-08-0/Carbon Monoxide; 65277-42-1/Ketoconazole; 7782-44-7/Oxygen; 84625-61-6/Itraconazole; 9035-51-2/Cytochrome P-450 Enzyme System

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


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